CHAIRMAN
LASKEY:Good morning.I'd like to call this meeting to order.My name is Warren Laskey and pleased to
chair this morning's session.Our topic
this morning is a discussion of the pre-market application for the Revelation_
Tx Microcatheterwith NavAblatorTM
RF Ablation System P020039.Geretta, if
you could please read the Conflict of Interest statement.

MS.
WOOD:The following announcement
addresses Conflict of Interest issues associated with this meeting and is made
part of the record to preclude even the appearance of an impropriety.To determine if any conflict existed, the
Agency reviewed the submitted agenda for this meeting and all financial
interests reported by the Committee participants.

The
Conflict of Interest statutes prohibit special Government employee from
participating in matters that could affect their or their employers' financial
interests.The Agency has determined,
however, that the participation of certain members and consultants, the need
for whose services outweighs the potential conflict of interest involved is in
the best interest of the Government.Therefore, waivers have been granted for Drs. David Schwartzman and
Albert Waldo for their interests in firms that could be affected by the Panel's
recommendations.

Dr.
Schwartzman's waiver involves consulting on a competitor's unrelated product
for which he receives an annual fee of less than $10,001.Dr. Waldo's waiver involves consulting on a
competitor's unrelated product for which he receives an annual fee of less than
$10,001 and also consulting with a competitor on unrelated matters for which he
receives an annual fee of less than $10,001.The waivers allow these individuals to participate fully in today's deliberations.Copies of these waivers may be obtained from
the Agency's Freedom of Information Office, Room 12A-15 of the Parklawn
Building.

We
would like to note for the record that the Agency took into consideration other
matters involving Drs. Waldo, Schwartzman, Cynthia Tracy and F. Roosevelt
Gilliam.Each of these panelists
reported past or current interests involving firms at issue but in matters not
related to today's agenda.The Agency
has determined therefore that they may participate fully in all
discussions.We would also like to note
that Michael Morton, the Industry Representative for the Panel, has reported
interests in firms at issue.

In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participate has a financial interest, the
participant should excuse himself/herself from such involvement and the
exclusion will be noted for the record.With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose any
current or previous financial involvement with any firm whose products they may
wish to comment upon.

CHAIRMAN
LASKEY:Thank you, Geretta.I would like to have the table up front
introduce themselves beginning to my right please.

MR.
MORTON:Michael Morton, I'm an employee
of Sorin-COBE and I'm the Industry Representative.

CHAIRMAN
LASKEY:Thank you, Members.I understand that there will be some
additional folks showing up.There's
been an accident outside so we'll have some more people coming in later.We can introduce them at that point.Geretta, if you couldread the voting status statement please.

MS.
WOOD:Pursuant to the authority granted
under the Medical Devices Advisory Charter dated October 27, 1990 and as
amended, August 18, 1999, I appoint the following individuals as voting members
of the Circulatory System Devices Panel for this meeting on May 29, 2003:Sharon-Lise Normand, Ph.D.; Christopher J.
White, M.D.; Alberto L. Waldo, M.D.; Francis R. Gilliam III, M.D.; David S.
Schwartzman, M.D.; Thomas Ferguson, M.D.; William Maisel, M.D. M.P.H.For the record, these individuals are
special Government employees and are consultants to this Panel under the
Medical Devices Advisory Committee.They have undergone the customary conflict of interest review and have
received the material to be considered at this meeting.

In
addition, I appoint Warren K. Laskey, M.D. to act as temporary Chairperson for
the duration of this meeting.This is
signed by David W. Feigal Jr., M.D. M.Ph., Director, Center for Devices in
Radiological Health and dated May 27, 2003.

CHAIRMAN
LASKEY:Thank you.Before we commence with the topic of the
day, there will be a brief presentation from the Office of Surveillance and
Biometrics on the topic of "Diathermy Interactions with Implanted Leads
and Implanted Systems with Leads".So if we can have Marian Kroen.

MS.
KROEN:Good morning.I'm Marian Kroen with the Issues Management
Staff.The Staff was charged with among
other things facilitating centered discussions and evaluations of high profile
public health issues through our center wide expert committee meetings.As part of a new initiative to periodically
brief panels on important topics, I was asked to make this presentation to you
on "Diathermy Interactions with Implanted Leads and Implanted Systems with
Leads".

FDA
learned of two adverse events.Both of
these were interactions of diathermy therapy in patients with deep brain
stimulators.Two patients had received
shortwave diathermy, one patient treated after oral surgery for a pulled tooth
and another patient was treated at the middle back region.Both patients went into a coma and
subsequently died.

So
what is deep brain stimulation?Basically there's a stimulator or pulse generator implanted around the
clavicle and leads snake up through the neck and go to an electrode which is
implanted in the brain.It's typically
used to treat Parkinson's disease and other conditions.

What
is diathermy?Diathermy can be thought
of as an electromagnetic heating pad.But while a heating pad heats just the skin, this heats inside the body.Diathermy means deep heat but it can be used
in both heating and non-heating modes.It's used for relief from pain with strains, sprains, bursitis and
muscle spasms.

Here
is a picture of a diathermy unit and a patient receiving diathermy.Diathermy units can come with one or two
applicator heads which can be positioned over the patient in appropriate
positions.

Who
uses this?Diathermy is used by
physical therapists, occupational therapists, sports trainers and others.

There
are three kinds of diathermy: shortwave which is also called radio frequency,
microwave and ultrasound.

When
FDA learned of these two adverse events, an expert committee was formed.In parallel to this, Medtronic performed
some testing.Medtronic was the
manufacturer of the deep brain stimulators.They did some in vitro testing using their deep brain stimulator and the
model of diathermy that was used in one of the adverse events.

The
result was that there was a temperature rise of 55 degrees Centigrade
("C")at the DBS lead during a 15 minute diathermy exposure at maximum
diathermy settings.As you all know,
cardiac ablation happens around 50 to 55 degrees C.There was a temperature rise at 27 degrees C at the settings for
the adverse event.Again this is a
temperature rise from ambient temperature.

So
the expert committee sat around and said "What kind of information do we
need".And we decided that we
really needed to find out how big this problem is and what's the scope.We needed more testing to determine
this.Are all implants affected?Are all metal implants affected?Is the problem with only active implants and
does the shape of the metal implants matter?

We
had OST test active implants.OST is
the Center's Office of Science and Technology.They do testing and stimulations in support of FDA's missions.They tested a spinal cord stimulator and a
cardiac pacemaker system using a test set up which is similar to
Medtronics.They found that the
temperature rise at the lead electrode is high.The temperature rise occurs whether or not a pacemaker is
connected.So really it's just the lead
that's causing this temperature rise.

The
cardiac lead in pacemaker systems showed the highest temperature rise of 48.8
degrees Centigrade.The spinal cord
stimulator had the second highest temperature rise of 27 degrees C and the
temperature rise was highest where a shallowly implanted lead was
simulated.It's interesting to note
that while Medtronics tested a 15 minute diathermy session, OST tested for a
minute or two.They plotted the
temperature rise and they tested until the rise flattened out.So this would encompass around 90 percent of
the temperature rise.If you did 100
percent of the temperature rise, the temperature at the lead tip for the
pacemaker would be around 54 degrees Centigrade.

OST
also tested non-active implants to see whether they had an effect.We really found that there was minimal
heating of one to four degrees C.We
tested mainly orthopedic implants of various shapes and sizes to see if they
had any effects.This included screws
and plates and titanium and stainless steel rods.We concluded that diathermy interactions with dangerously high
temperatures were limited to implantable systems with metallic leads and the
implanted leads themselves.

The
theory is that the implanted lead acts like an antenna to receive the radiated
energy from the diathermy.The power is
dissipated.It's collected all along
the lead but it's only dissipatedwhere
there isn't any insulation which is the electrodes. So the current
density and thus the temperature at the lead electrodes can be very high due to
the small surface area of the electrodes.

Can
all types of diathermy cause this interaction?Both the shortwave and microwave diathermy produce an electromagnetic
field which can interact with implanted leads.But ultrasound diathermy would have a different mode of
interaction.It has a mechanical
vibration rather than an electromagnetic field.

So
what did FDA do?We reached into our
toolbox and took some actions.We
recommend that the labeling on metallic leads and lead systems have a warning
against patients with implanted leads.Pacemakers had this warning for eons.Labeling on diathermy equipment had a contraindication against use on
patients with implanted leads.

The
FDA issued a public health notification which was distributed both to
implanting physicians and diathermy endusers.A journal article is in the process of being processed.An issue of "Patient Safety News"
was devoted to this."Patient
Safety News" is a televised series that satellite broadcasts to hospitals
and other healthcare facilities.

But
there's an interesting question here.Why are there no injuries from pacemakers?We have testing that shows that the pace lead electrode
temperatures are high, high enough to cause tissue damage. There had
certainly been a long enough history of pacemakers and leads for this
interaction to have shown up.There
have been two reports of damage to the pacemaker but not to the heart with
diathermy use.

So
we have some possible reasons why we haven't seen any of this.First is the warning may be adequate but as
we all know, who reads the labeling?Another thing might be that the blood flow in the heart carries away the
heat.This is true but blood flow in
the heart also carries away the heat in cardiac ablation and that seems to kill
tissues so why would it not kill tissue in this instance.

Next
is the distance.Maybe the distance is
sufficient to stop damage but we believe the distance of the patient who got
diathermy in his mid back is greater than the distance from a pacemaker to a
diathermy unit.

What
I think really happens is damage but nobody had really put two and two
together.A patient might go to the
doctor and present with loss of sensing or failure to capture and the physician
might reposition the leads.The
physician didn't know since this hadn't been publicized to ask the patient
whether they had diathermy and the patient didn't volunteer that they had
diathermy so they just repositioned the lead and went on.

Another
theory is that the brain has no pain receptors and other parts of the body
do.If a patient has pain receptors,
they can tell the diathermy administrator to lower the settings or stop the
diathermy unit.Your thoughts and
comments are welcome.Thank you.

CHAIRMAN
LASKEY:Thank you, Marian.I guess we will spend a couple of minutes
responding. For openers, I don't know if any of those explanations make sense
other than the conductive capacity of the heart within the ventricle but it's
not a trivial exercise to reposition a lead.I think you would have heard more about that if this was really more
than a curiosity. Do my colleagues have any thoughts?

DR.
SCHWARTZMAN:Can you tell us more about
the nature of the brain injuries that were associated with those deaths?

MS.
KROEN:I'm not really that familiar
with it.There was an autopsy and it
showed edema andnecrotic tissue around
the lead electrodes but that's all I know.Some representatives from Medtronic are here and they don't know
anything more about it either.

DR.
TRACY:Was there disruption of the lead
or is there thought that the diathermy is causing damage at the tip of the
electrode?

MS.
KROEN:There was no disruption of the lead.It is at the lead electrode.

DR.
TRACY:So you might not know if an
ablation took place at the tip of a pacemaker lead as long as it didn't damage
things enough so that you lost capture.You might never know.

MS.
KROEN:That's correct.

DR.
TRACY:And not everybody feels pain
with an ablation.Most do but everybody
does.It depends on the location of the
energy delivery so you might have something that you can't really detect.

MS.
KROEN:That's true.

DR.
GILLIAM:Short of the dysfunction of
the pacemaker, I'm not sure how you'd even know that in pacing just because we
ablate with the threshold safety margins we have.It probably could go undetected unless you really created a major
lesion.So I wouldn't take shelter in
the safety that we haven't had the complaints.It concerns me greatly actually.

CHAIRMAN
LASKEY:Do you have any idea what the
average number of diathermy sessions per individual is?

MS.
KROEN:We don't know.We do that there are chronic pain
institutions.They use diathermy quite
a lot.I don't know how many pacemaker
patients they have but they told me that they've been advocating that
pacemakers patients not have this for a long time and had no evidence to back
it up.They say they get thousands of
hits a day on their site.

DR.
GILLIAM:Did they do any work with the
defibrillator patients at all?Was
there any suggestion along that line?We have mentioned pacemaker but it would seem to me that the
defibrillator may have a bigger antenna.

MS.
KROEN:They may have a bigger antenna
but I think the critical issue is how big the electrode is.I believe the electrode is bigger so it
would have a larger area to dissipate the energy.Therefore it wouldn't be as intense and not as hot as the
pacemaker lead electrode.

DR.
GILLIAM:I guess there are multiple
electrodes on a defibrillator.There
are some very large ones but they are also smaller points.I'm just looking at a lot of the measurement
data that we have.It's a bit more
interactive in a defibrillator.We may
be able to evaluate other parameters such R-waves or atrial waves and P-waves.

MS.
KROEN:Paul, would you know if there
are multiple electrodes would the temperature be dissipated among all of the
electrodes?

PAUL
(tan jacket):I'm Paul Rejaric (PH) of
OST.I did the in vitro studies.What we saw with the spinal cord stimulator
which is four leads, four electrodes, is that it was distributed among the
leads.The report that she gave you
today was that the temperature was at the lead at the tip.Then as you went down, the temperature
progressively actually got less.

We
did find that the area is very definitely a problem.The reason why we saw higher pacemaker one was because the
electrode itself was very small compared to the spine cord stimulator lead
actually.So it's a surface area energy
deposition problem.

CHAIRMAN
LASKEY:Well, I'm not sure you're
getting a lot of comments from the panel.I guess if you're interested in an inquiry, you go where the money is
which is some of these centers where they do a lot of diathermy and do an
observational study looking specifically for people with pacemakers which
shouldn't be hard.

DR.
GILLIAM:Is there a distance from the
electrode that you have to be?What's
the fall off?If you are within two or
three inches, is there a greater amount than as opposed to 15 or 20
inches?Is there a safe distance to be
away from it that you wouldn't get this even in a pacemaker lead?

PAUL
(Tan coat):We did all of our tests
very close.The only reason we did it
close was because we were looking at the brain stimulator simulation where they
put the thing very close.Ours
basically were a half centimeter away which is very close.As we dropped, we dropped down to five
centimeters at one point and virtually that knocked away all the heating.

It's
a question of how well do you couple.How is the thing oriented?We
find for example if you oriented a certain way, you actually get no coupling at
all which is true with any antenna.It's all a problem of probability.Had the person turned the lead the other way he still would have gotten
the heating but probably not even bother the patient.It's just one of those things.

MS.
KROEN:I would also add here that again
one of the patients had diathermy to the mid back and the electrodes were in
the brain.That's quite a fair
distance.So we really don't know what
a safe distance would be.

CHAIRMAN
LASKEY:All right.Thank you.We're puzzled as well.I would
like to move on to the topic at hand and begin with the open public
hearing.I would like to invite anyone
from the audience who wishes to address the panel on today's topic to please
approach the podium and identify yourself.If not, then I will close the open public hearing and we'll move to the
sponsor's presentation. Geretta.

MS.
WOOD:I would just like to remind the
speakers to introduce themselves and state their conflict of interest before
presenting.

MS.
BALDWIN:Good morning, ladies and
gentlemen, members of the Panel. My
name is Marianne Baldwin.I'm with
Cardima.I'm here today to presentto you the results of a very complex study
of a very complex disease, Atrial Fibrillation.

I'm
going to start just by introducing the people who will be speaking for Cardima
today on the Treatment Options of Atrial Fibrillation, Dr. Neal Kay, on the
Preclinical Studies and the Protocol Development for the Clinical Studies, Dr.
Hugh Calkins, the Results of the Clinical Studies, Dr. Abraham Kocheril, our
primary investigator, and the Conclusions and wrap-up again by Dr. Kay.

Just
as a brief background since 1993, Cardima has been developing, manufacturing
and marketing catheter-based systems for the Electrophysiological field
exclusively.The catheters include the
PATHFINDERTM family of mapping devices, the VENAPORT_, VUEPORT_ and
NAVIPORT_ guiding catheters and the REVELATION_ family of mapping and ablation
systems which represent the system under review today.

Currently
the company is marketing its diagnostic and guiding catheters in the U.S.A.,
Canada and the European Union and Japan.The REVELATION_ family of mapping and ablation devices are marketed in
Canada and the European Union.

This
is a listing of our currently available products in the U.S.The initial strategic plan for Cardima was
to introduce the mapping and guiding systems before the therapeutic devices to
allow time for the physicians get comfortable with the smaller devices.510k clearance was obtained for the
diagnostic and guiding catheters being in 1995 with the VENAPORT_.Four years later this entire list was
cleared.

These
are illustrations of our catheters.This is the guiding catheter of the NAVIPORT_ an 8.0 French device.This device is used to deliver the
REVELATION Tx the device we'll be studying today as part of the investigational
system although this device has been cleared.It was the first deflectable guiding catheter on the market.The VUEPORT_, its predecessor on the right
is practical to obtain good venagrams.We've had 20,000 of these units distributed.

This
is the NavAblatorTM, Cardima's four millimeter hot tip developed
specifically for this study to create lesions at the isthmus line.

This
is the PATHFINDERTM, examples of thecatheters that have designed to access coronary sinus and its
feeders.The 1.5 mini PATHFINDERTM
is useful for mapping small vessels such as Vein of Marshall.Our standard PATHFINDERTM on the
right, the 2.5 French, maps the coronary sinus and the feeders.Physicians have been using it lately for the
placement of pacemaker leads.Cardima
performed a clinical study for the PATHFINDERTM to demonstrate its
ability to map effectively.We have
distributed 20,000 units of these devices.

The
REVELATION_ Tx, the device shown on the left there, is a 3.7 French device to
map and ablate.Its sister device for
pulmonary veins is distributed in Europe and that's a 4 French.The AD-deflectable of the 3.7 French device
is also distributed in Europe.

This
is a description of the differences and the unique features of Cardima's core
technology.The principal
distinguishing feature is that it incorporates a guide wire technology that was
developed for angioplasty permitting a variable stiffness of the guide wire
that allows construction of a very flexible and compliant distal segment.It's a composite shaft that includes
conductors tightly braided over the core wire and the structure is encapsulated
in polyethylene before being coated with a hydrophilic lubricant.

The
other really key feature is the fine wire coiled electrode located along the
distal segment.We have eight
electrodes on this catheter arranged in linear array allowing the catheter to
maintain good contact with the wall of the beating heart.It also permits these small electrodes the
catheter to ablate with greater current density and requiring less power.

Just
to illustrate and compare the lesion shape of this catheter to a hot tip
catheter, you'll see that there is similar depth but a significant difference
in the width.Preservation of myocardium
is a result of this and was one of the features of this design.

Here
we have a segment of the linear array with three electrodes shown and four
thermocouples in the middle.You'll see
that the lesion formation overlaps the thermocouples.You have a continuous lesion there.We can ablate with between seven to 35 watts of power.

Last
but not least, Cardima's indications for use are treatment of atrial
fibrillation in patients with drug refractory paroxysmal atrial fibrillation by
mapping, pacing and ablating with a set of lesions in the right atrium.

Now
Dr. Kay will present to you Treatment Options on Atrial Fibrillation.Thank you.

DR.
KAY:Thank you very much.My name isNeal Kay.I'm from the
University of Alabama.I have no
financial interests in Cardima.I'm not
an investigator and I'm not a consultant.I'm being paid for my time today however.

Atrial
fibrillation as we all know is a huge problem and there probably are as many
treatments for this problem as there are patients who have it.This slide just shows the magnitude of the
problem as it relates to age.As the
population ages, you see that the absolute number of patients with Atrial
fibrillation is increasing and both the incidence and prevalence go up with
age.So this is becoming more and more
of a problem

It's
a complex rhythm and not every kind of atrial fibrillation is the same as every
other kind.The ACC/AHA have recognized
this and have proposed the following classification scheme.Patients may present with their first
episode of detected atrial fibrillation in which case the subsequent course is
not known.Then they may go on to have
paroxysmal atrial fibrillation which are those that terminate spontaneously or
have persistent atrial fibrillation, those episodes that require cardioversion
or some drug intervention to terminate and do not terminate spontaneously.

Then
finally there is this permanent atrial fibrillation which atrial fibrillation
that is refractory to cardioversion or atrial fibrillation that in the opinion
of the patient and their physician where it's just hopeless to try to maintain
sinus rhythm.So it's a complex
problem.

There
are significant limitations with drug therapy.Shown here in this slide is just the results of one prospective trial
looking at different doses of Sotalol vs. Placebo in the recurrence of atrial
fibrillation.As you can see, there is
a high risk of recurrence even on fairly large doses of Sotalol to maintain
sinus rhythm.At six months, less than
half the patients will have persistence of sinus rhythm.

Similarly
the Canadian Trial of Atrial Fibrillation ("CTAF") look at different
drugs after cardioversion as you can see.I think we all know that Amiodarone is more effective than other
antiarrhythmic medications.It's more
effective than Propafenone or Sotalol.But even so, many patients will have recurrence of atrial fibrillation.

The
drugs that we use have limitations.The
limitations are largely a function of the kind of underlying heart
disease.These are the ACC/AHA
guidelines.For example, patients who
have congestive heart failure, it's recommended by the ACC/AHA that probably
Amiodarone and Dofetilide may be the only drugs that may be used safety.

For
patients with coronary artery disease, there's a significant limitation in the
use of Type 1C drugs.So this scheme
has been proposed that we perhaps start with Sotalol and then perhaps go to
Amiodarone or Dofetilide and finally non-pharmacologic options can be
considered.

Hypertension
and specifically Left Ventricular Hypertrophy present problems with drugs that
prolong the QT interval.When there is
significant Left Ventricular Hypertrophy, we may be limited to the use of
Amiodarone.For patients who don't have
significant structural heart disease and just have hypertension, the Type 1C
probably are reasonably safe to use followed by Amiodarone, Sotalol or
Dofetilide.

This
slide is presented to highlight the importance of the pulmonary veins in the
initiation of atrial fibrillation.Here
is our surface intercardioelectrograms from a patient with the spontaneous
onset of atrial fibrillation that arises in this case from a pulmonary
veinIn this case it's the right
superior pulmonary vein.You see an
arrow here indicating the first onset of electrical activity in the pulmonary
vein.It comes from the pulmonary vein
to the left atrium and then subsequently to the right atrium.So the pulmonary veins appear to be
important in the initiation at least of atrial fibrillation.

Arial
fibrillation ablation is currently being practiced around the world in
relatively limited of centers.The most
common technique is shown here with a circular mapping catheter place at the
ostium of the pulmonary vein to guide recognition of sites of early activation
between the pulmonary vein and the left atrium.A radio-frequency catheter is placed just proximal to that
mapping catheter and radio-frequency current is delivered with the goal being
to electrically isolate the pulmonary vein.

This
just shows an example of that.On the
bottom tracings in green, you see pulmonary vein potentials and radio-frequency
current applied.Finally after the
onset of RF, we see that there is disappearance of pulmonary vein
potentials.That is how this technique
is being applied most commonly to ablate atrial fibrillation now throughout the
world.

There
are some significant limitations to pulmonary vein ablation that I want to
highlight.One of these is the
occurrence of this complication which is pulmonary vein stenosis. This is
a right superior pulmonary vein. There is significant narrowing of the
pulmonary vein just at the ostium as it joins the left atrium.This is an important and potentially
devastating complication of ablation in the left atrium.

These
results here published about a year ago are fairly typical of those that are
seen in most of the large centers doing this procedure.You see that for patients who have
paroxysmal atrial fibrillation about 70 percent of the patients can be rendered
free of reoccurrence at least in the immediate term.

On
the dotted line, you will see that the results for persistent atrial
fibrillation really are not as good with only a small minority of the patients
having control of their atrial fibrillation with a pulmonary vein isolation
procedure if they have persistent AF.

AF
ablation does have significant limitations.I just want to highlight them.Pulmonary vein isolation is only effective in about two-thirds of
patients with paroxysmal AF.It's less
effective in patients with more advanced forms of atrial fibrillation.

There
are significant risks and these are likely to be operator dependent.Pulmonary vein stenosis has been reported to
occur anywhere from one percent to eight percent and clearly seems to have a
relationship to the experience of the operator.There's a risk of stroke that ranges from about one percent to
four percent.

Pericardial
tamponade again in the same range.Major bleeding complications can and do occur and they are related to
the large amounts of anti-coagulation that are generally required to required
to ablate on the left side.Importantly, it's limited to physicians who feel competent to perform
transeptal catherization.Therefore it
presently is not widely applicable.

I
would like to highlight that there really have been no multi-center prospective
trials of pulmonary vein isolation to this point.So it is likely that the complications that have been reported in
single center series probably are actually higher when we finally start to do multi-center
prospective trials.

This
slide just shows the results of four surgical strategies to treat atrial
fibrillation.Here in the top left is
what is called the Cox-Maze operation which is bi-atrial operation involving
incisions around the pulmonary veins and also incisions in the left atrium and
importantly in the right atrium.The
percentages are the percentage of patients who are rendered free of atrial
fibrillation by the surgery.You can
see that this probably is the best results that have been achieved which is
with this bi-atrial surgery.

The
other tracings show the results from different investigators looking at purely
left atrial ablation procedures at surgery.As you can see, the results aren't as good.So it does appear that if you surgery ablate in both atriums the
outcome appears to be better than in just the left atrium alone.

How
does surgery work?It probably works by
at least two different mechanisms.One
of those is that it probably prevents pulmonary vein triggers by encircling the
pulmonary veins but the incisions in the atrium probably interrupt
macroreentry.We know that most atrial
fibrillation is maintained by relatively large macroreentry circuits at least
in our studies on the size of about nine centimeters.Surgery may help to prevent these by preventing the real estate
that's available to maintain macroreentry circuits.

Now
I've shown you some reasons why the pulmonary veins are probably very
important.I've also shown you some
reasons why operations involving both atria may be better than just the left
atrium.Here are some results reported
from Japan looking at their results with the Cox Maze 3 operation which again
these first two columns are bi-atrial operations and just the right atrial Maze
operation along.As you can see, the
results are clearly better when two atria are operated on.

But
there is at least a moderate degree of success with just a right atrial Maze
operation done surgically.So it does
raise the possibility that a right atrial operation may have some role to play
in the prevention of atrial fibrillation.

As
I've shown you the results at least from surgery, these results demonstrates
that there may be a place for a right atrial ablation alone and I think Cardima
will now presents some results showing that there is indeed a role for this
approach in a prospective clinical trial.Thank you.

DR.
CALKINS:Good morning.My name is Hugh Calkins and I would like to
present some of the animal work that has been done with this system as well as
the study design.

MS.
WOOD:Dr. Calkins, please state your
relationship to the sponsor.

DR.
CALKINS:I've been involved with animal
studies with Cardima about three or four years ago.I also was a clinical investigator in this clinical trial and
I've been paid for my time for being here today.I'm not an equity owner in the company.

The
Pre-Clinical Studies have been performed which have demonstrated that the
Cardima REVELATION_ system is biocompatible.It's compliant with applicable ISO requirements.It also has been demonstrated that this is a
reliable catheter be it again compliant with the mechanical and electrical
performance requirements of the Massi guidelines.

Now
a large number of animal studies have been performed with the Cardima
REVELATION_ ablation system and they are summarized on this slide.The system has been worked at the
Massachusetts General by David Kean, M.D.

Other
animal studies have been performed by Dr. Mauricio Arruda at the University of
Oklahoma in both a thigh muscle preparation and the dog preparation.Then additional studies were performed at
the Mayo Clinical by Drs. Asirvatham andDoug Packer and also at Johns Hopkins.I would like to highlight the results of some of these for you today.

The
study that was done by David Keane who was really first to work with this
catheter was performed in an AF goat model where they demonstrated that AF
could be induced at baseline and then delivered the four lesions that are part
of this study design today and showed that AF was no longer inducible after
delivery of these linear lesions.They
also showed that these lesions were frequently transmural in nature.

The
studies done at the Mayo Clinic were interesting.They look at 14 dogs. Their objection was to compare the
linear microcatheter system with the linear standard ablation system where you
have standard 4 millimeter 7 French electrodes lined up along a multipolar
catheter.They created 30 lesions with
the Cardima system and 36 linear lesions with the alternate catheter system.

The
results are summarized here that the lesions were slightly narrower with the
Cardima microcatheter system with a standard 7 French system.The lesions had similar depth.The volume was less with the Cardima system
as you would expect given that it had smaller width.Importantly the presence oflesion formation was the same, 98 versus 95 percent.Lesion was transmural in a similar portion,
89 percent and 85 percent.

Dr.
Arruda looked at the NavAblator system, the hot tip, flutter line catheter in
six dogs and showed that this indeed was able to ablate the isthmus.Isthmus block was achieved in five of six
dogs.The typical lesions were created
with this 4 millimeter standard ablation catheter.

The
study I'm most familiar with is the study we performed at Hopkins in 10
dogs.When I heard about this ablation
system, I was somewhat skeptical that a small 3.7 French catheter could really
create linear lesions and it could create deep lesions.I said "Why don't you let me do a
little study in our own animal laboratory where we can compare head to head
with standard ablation technology using a 4 millimeter catheter with a drag and
pullback approach versus the Cardima system".

I
set out about to do this again creatingfour linear lesions in the right atrium of these dogs.The dogs were survived one month and then
they were sacrificed and the lesion characteristics were compared.This slide shows what we found with the
standard 4 millimeter catheters using the sheath and pulling it back point by
point trying to make linear lesions.What you can see on the left side of this screen is what happens on a
good day where here's one lesion and here's a second lesion and here's a third
lesion.We all would agree that this is
a linear lesion as far as we can see.

But
what we saw more commonly was this kind of thing where you have one lesion
here, one lesion here, a third lesion here and then you had a clear gap between
the lines.Then we also commonly saw
what you see in the third which looks like a gunshot blast where you have one
lesion here, one lesion here, one lesion here, one lesion here, nothing
continuous or linear about it.Whether
these lesions are in fact pro-rhythmic, anti-arrhythmic, who really knows.

Now
you compare that with what we saw with the Cardima system and there was a
striking difference.Here's a linear
lesion created with a system that is thin and linear and this is on the free
wall of the atrium.Here's a line along
the septum going through the coronary sinus os going down to the inferior vena
cava.Here's a flutter line from the
tricuspid valve back to the inferior vena cava again a thin linear lesion.

Now
when we looked at these lesions histologically, we found that they were
narrower than standard RF lesions as we expect.

We
found that there was no difference in the overall length from start to finish
of these lesions.They tended to be
longer than the drag and pull lesions but this was not statistically
significant.They had a similar length than
what we created with the standard catheter.

When
you looked at depth, there was no difference.Perhaps the Cardima lesions were a little bit deeper.I think this was one of the most important
findings of the study.

Then
when we looked at things like lesion linearity, were the lesions delivered in a
linear fashion, all the Cardima lesions were linear versus only 37 percent of
the drag and pull lesions.

When
we looked at continuity, were the lesions continuous, 72 percent of the Cardima
lesions versus 37 percent with the standard drag and pull approach.

Finally
when we looked at anchoring to anatomic structure to the SVC or the IVC, we had
92 percent anchoring versus 62 percent anchoring again very different result.

We
concluded that atrial lesions created using the Cardima system are narrower,
more continuous, more linear and more likely to anchored to an anatomic
structure than those created with a standard ablation catheter using a drag and
pull approach.These differences in
lesion characteristics may facilitate cure of atrial fibrillation with a
catheter based Maze procedure.

Now
I want to go over to how the protocol came to be and how the study was
designed.When the study was designed,
the question was where to start.Do we
do an left atrial procedure, a right atrial procedure?These discussions were really between
Cardima and Massachusetts General who was very heavily involved at that
point.David Keane was one of the early
investigators with the system and the FDA.

It
was considered that the optimal lesion set for atrial fibrillation treatment
wasn't really known.We knew that Cox
Maze procedure was effective when you did all the lesions.But if you take them away and peel them
back, what was the least number of lesions you need to see effect?

We
now know which we learned that safety and efficacy of pulmonary vein isolation
was unknown then and it's unknown now.When this clinical trial started, that wasn't even on the horizons.Nobody even knew about the pulmonary veins
at that point.The most important thing
was that safety first above all do no harm and that right atrial ablation is
likely to be lower risk than working the left atrium both in terms of
thrombo-embolic complications and also the complications associated with a
transeptal technique.For that reason,
it may be more widely applicable in the AP community.

This
is how the study was developed.Theinitial study design was
performed six years ago in 1996 again between the MGH, FDA and Cardima.
They were in discussions at that point.Phase Ia was just a mapping phase started in 1997 with the PATHFINDERTM
was similar to the REVELATION_ catheter without the thermocouples.

Phase
IIa started in 1998 and that's the early ablation part of the study.In 1998 is when the Circulatory Systems
Advisory Panel first met to get advice regarding how to design atrial
fibrillation studies.Although the
Cardima study was designed prior to this meeting, the study design was
consistent with it.Phase IIb which is
part of the phase included in the results presented today started in 1998.Mapping and ablation was performed again
with the REVELATION_ catheter.

The
second Advisory Systems Panel met in 2000 and additional discussions were made
about design of atrial fibrillation trials.Then Phase III was started in 2000 and the main difference was the
addition of the NavAblatorTM catheter, the standard deflectable hot
tip catheter, to the protocol for Phase III.

When
you look at the recommendations that were made by the FDA Advisory Panel at
that time, they recommended a single arm non-randomized study.They recommended that patients serve as
their own control, that patients should have failed at least two or more
anti-arrhythmic drugs or amiodarone and that they should have had two episodes
of atrial fibrillation over a three month period.

The
Cardima study design was designed in consistency with each of these
recommendations.But importantly
instead of having two episodes of atrial fibrillation over three months, they
had three episodes documented over one month to get in their study to be sure
that this was a highly symptomatic patient population.

The
Advisory Panel recommended that an appropriate endpoint would be a 50 to 75
percent reduction in the frequency of symptomatic atrial fibrillation episodes
and that six months was a reasonable timepoint for evaluation of therapy
effectiveness.Safety was obviously
important as was quality of life.Again
these were included in the study design of this protocol that you will hear
about this morning.

The
objective of the study was to determine if the REVELATION_ ablation system
successfully and safely reduced the number of symptomatic atrial fibrillation
episodes, that it was safe and that it improved the quality of life.

The
inclusion criteria is summarized here. Again there was three or more
symptomatic episodes of atrial fibrillation documented by an event monitor in
the 30 days prior to enrollment and prior to the procedure. They had to
be refractory to two or more anti-arrhythmics or refractory to amiodarone
alone.They had to have no significant
structural heart disease or marginal heart disease.The left atrial size had to be less than five centimeters.They had to have no echocardiographic
evidence of an intra-atrial thrombus or an ASD or PFO on a
trans-esophagealechocardiogram.

Some
of the pertinent exclusion criteria are here: acute ablation failure within two
months, MI within six weeks, CVA or TIA within six months, pregnancy or
coagulopathy that was known.

This
slide goes over the general scheme of the study.Patients were approached for entry into the study and form
consent was obtained.They then were
enrolled in a 30 day monitoring period where they were given an event monitor
and were instructed to transmit their episodes of atrial fibrillation.They were not told they had to cross a
certain bar to get in but they were just provided with this event monitor.

If
they met the three episodes in two months, then the ablation procedure was
performed.They had a TEE performed
prior to this.Then after catheter
ablation, they were followed prior to discharge in the one, three, six and
twelve months.If they didn't meet the initial
screening phase, if they did not have three episodes documented in one month,
they could have another screening phase where they would have to have nine
episodes documented over three months.So some patients were able to get in at that point in the study.

This
slide summarized the lesion sets that were delivered.There were three lesion sets that were part of the protocol.One was the post-lateral line from the
superior vena cava back to the inferior vena cava posteriorly and
laterally.Second was a standard
isthmus or flutter line.The third was
the septal line from SVC to the IVC along the septum through the coronary sinus
through the frame and the valley and down to the inferior vena cava.

Now
in Phase IIb there was an optional anterior line that was subsequently delayed
in Phase III both because it was delivering energy in the region in the sinus
node and also because it was not felt to be that critical to the
procedure.The whole idea was to have a
procedure that could be accomplished in a short period of time.So we settled on the three A, B and C
lesions summarized in this slide.

This
just shows the patient follow-up that was performed.Again patients had a history, physical exam, 12-Lead EKG at
baseline and at office visits at one, three, six and 12 months after ablation.The TEE was done prior to the ablation
procedure.The echocardiogram and
stress test was performed at baseline and three months.

An
event monitor was performed weekly and with symptomatic episodes of atrial
fibrillation at baseline and at months one, three and six.Patients completed quality of life
questionnaires with both SF-36 and atrial fibrillation severity score at
baseline, at three and six months following ablation.Then they had a telephone interview at 24 months.

The
primary clinical endpoints as defined in the study protocol initially submitted
to the FDA was the reduction in the frequency of spontaneous atrial
fibrillation episodes and also to look at the incidence of adverse
effects.The secondary endpoint was the
quality of life on the on the SF-36 or the atrial fibrillation severity scale.

The
acute procedural success criteria wasa
reduction in amplitude, fragmentation or widening of the local electrograms,
appearance of split potentials and/or an increase in the pacing threshold
following ablation.Then the long term
endpoints or the primary endpoint was a 50 percent reduction in symptomatic
atrial fibrillation episodes for patients with more than five episodes per
month during the screening period.Then
for patients who had less episodes of atrial fibrillation, only three or four
episodes, they would have to demonstrate a 75 percent reduction to meet the
effectiveness endpoint.

Clinical
success was defined as reduction ain atrial fibrillation episodes while
maintaining the same anti-arrhythmic drug regimen or a reduced dosage of the
drug regimen during the follow-up.

The
sample size was determined to be 80 evaluable subjects at six months based on
an estimated patient success rate and statistical considerations. This sample
size was specified again in protocol submitted to the FDA and approved prior to
initiation of this study.

In
summary, multiple animal studies have demonstrated safe creation of thin,
transmural, linearlesions with a
REVELATIONTM ablation system.This clinical study was designed in collaboration with the FDA.The clinical study incorporates a large
number of measures of safety and efficacy.Importantly as the first atrial fibrillation clinical trial, this study
is clearly charting new waters.Thank
you for your attention.I would like
now to introduce Dr. Abraham Kocheril who is the principal investigator of this
study.He's from the Carle Clinic and
he will bepresenting the study results
to you.

DR.
KOCHERIL:Good morning, everyone.My name is Abe Kocheril.I was the principal investigator of the
study.I'm being paid for my time and
expenses.I do not have equity interest
in the company.I will present to you
the patient population and study results.

Twenty
clinical sites took part in this trial.As you can see from this list, there was a mix of major university
centers as well as community hospitals.I think that speaks to the generalizability of the results that you are
about to see.

One
hundred and twenty patients underwent radio-frequency ablation according to the
protocol.There were eight patients who
withdrew within the six months of follow-up.There are 18 patients who have not completed six months of follow-up
which leaves 87 patients who have completed six months follow-up.These 87 are the subject of the
effectiveness analysis.The 120 who
underwent initial ablation are the subject of the safety analysis.

Looking
at the eight patients who withdrew prior to six months, four of these were
unable or unwilling to do follow-up.One of these patients had moved out of state.One had changed insurance carrier.Two others were simply unwilling to complywith the requirements of the study protocol.

The
other four had undergone AV node ablation and/or pacemaker implantation.There is a tendency to look at these as
failures.But I can tell you on one of
these patients what happened was that this patient had a single recurrence of
atrial fibrillation.After the ablation
procedure, the family convinced the patient to seek a second opinion.The physician rendering the second opinion
recommended AV node ablation and pacemaker implantation as the way to go.She did undergo this procedure.However in follow-up all the follow-up
tracings, all the follow-up pacemaker checks showed either sinus rhythm or an
atrial pace rhythm.

So
we start with the 87 patients who completed six months follow-up.Five of these had indeterminate baseline
episode data.One had indeterminate six
month episode data leaving 81 who were evaluable for primary effectiveness
endpoint.

The
baseline characteristics are shown on this slide.The mean age was 57.Seventy-seven percent of the patient were male.Seventy-two percent had prior cardiovascular
disease aside from their atrial fibrillation.Twenty-six percent had respiratory conditions.Twenty-six percent had endocrine conditions.Nineteen percent had neurologic
disease.Eighteen percent had renal
disease.So even though we tried
exclude people who had significant structural heart disease, we nonetheless
ended up witha group of patients who
did have some structural heart disease and had co-morbidities.

Twenty-eight
percent of the cohort had prior RF Ablation and I'll show more detail on
that.Eight percent had had bypass
surgery.Seven percent had DC
cardioversion before.Six percent
entered the study with a permanent pacemaker.Six percent more had percutaneous coronary interventions prior to
entering the study.

Looking
at the patients who had prior radio-frequency ablations, 22 patients had
ablation of atrial flutter prior to entering the study.Nineteen additionally had ablation of super
ventricular tachycardia or atrial tachycardia.

The
baseline arrhythmia symptoms are fairly typical for an atrial fibrillation
population.The most common symptom was
palpitations occurring in 87 percent.The second most common was fatigue occurring in 59 percent.Shortness of Breath in 50 percent,
lightheadedness in 37 percent.Nineteen
percent had chest discomfort and other symptoms were also reported.

The
baseline symptomatic atrial fibrillation episodes per month are shown on this
slide.Hugh Calkins already mentioned
the FDA Advisory Panel recommendation of a minimum of two episodes per three
months.That's the bar here for
reference.You can see from the
remainder of the bars that our study cohort easily exceeded that minimum.There was predominance of patients who had
five to nine episodes per month.The
range extended all the way up to 30 plus episodes per month.The mean was 10 episodes per month for the
study cohort.

Congruent
with the symptomatic episodes, there was a tendency to have a reduced quality
of life.This is the SF-36 domains
which is a nonspecific measure of quality of life.There was a trend towards a decrease in all of the categories but
particularly striking where the decreases in role, physical and vitality and
social functioning.As we'll show
later, there are the three parameters that tended to increase the most after an
ablation procedure.

Now
that you know who the patient population is, we'll move to study results.Dr. Calkins already mentioned the prescribed
studied lesions.These were the
post-lateral line A, the Septal line B, the isthmus line C and as was mentioned
line D was discouraged in Phase III of the protocol.As you can see on the right, line A was delivered in 90 percent
of these patients, Line B in 93 percent, line C in 90 percent.Only 8.7 percent received line D.The majority of the procedures were done
with lines A, B and C for a total of 83 percent.

The
mean procedure time was 250 minutes.That mean fluoroscopy time was 47 minutes.There is a bit of a learning curve in this.At my center we were able to complete these
procedures in about three hours with the fluoroscopy time of about 30 minutes.

Acute
procedural success is generally considered a surrogate for clinical
effectiveness.The initial plans to
record specific measurement of acute procedural success became unwieldy.Just to illustrate that, what we are dealing
with is an octopolar catheter.There
are eight electrodes.

It
usually takes more than one pass to complete each linear lesion so you are
looking at potentially 16 electrodes at which to do these analyses of decrease
in electrogram amplitude, fragmentation or widening of electrograms, possibly
measuring pacing thresholds.There are
three lines so that three times 16 is 48.If you do three measurements on each of those lesions, that's 144
measurements before you are done with the procedure. This really was unwieldy
so these were not consistently recorded.

However
in the EP community it is standard practice to look for reduction electrogram
amplitude, appearances with potential, etc. as measurements of lesion
adequacy.These were assessed in the
procedure.The investigators were asked
at the end of the procedure whether they had adequate lesion development.At the investigators' assessment, 110 out of
118 procedures were deemed successful for a rate of 93 percent.

Dr.
Calkins also mentioned that the primary endpoint was a symptom reduction endpoint.There was at least 50 percent reduction in
patients with five or more symptomatic AF episodes per month at baseline and 75
percent or greater in patients with three to four episodes per month at
baseline.Using this definition, 69 of
the 81 patients in the cohort or 85 percent were successful.

This
is an important slide showing symptomatic episode reduction from baseline to
six months.This shows each of the 81
patients individually.What you can
appreciate is that there is a striking and almost uniform decrease in symptoms
from baseline to six months.

Some
of the other salient features are that the people with the most symptoms, the
highest scores, are the ones who tended to benefit the most from the ablation
procedure.The other thing that you
will notice is that several of these subjects do approach zero episodes at the
six month mark.As an investigator,
these are very gratifying results.As a
clinician what this translates into is patients feeling better and not calling
in with symptoms.

This
is a different way of analyzing the atrial fibrillation frequency
reduction.This is looking at the
entire cohort.What you see is at
baseline there was 9.2 episodes per month on average. This was reduced by three
months to 3.5 episodes per month.At
six months, it was further reduced to 1.2 episodes per month.These are highly statistically significant
decreases from baseline with P values in the range of .0001.

There
were patients who were free of atrial fibrillation at six months.In fact 44 out of the 81 had no episodes at
six months for a rate of 54 percent.

Congruent
with this, there was a reduction in common arrhythmia symptoms.Graphed here are the various symptoms,
palpitations, fatigue, shortness of breath, lightheadedness, chest pain and
others.What you will see here is at
least a 50 percent reduction in most of these parameters with the exception of
chest pain and other.

A
pre-specified secondary endpoint of the study was quality of life.This was addressed by two measures. One is the atrial fibrillation severity
scales which is a measure specific to atrial fibrillation.The other is the less specific SF-36
domains.

In
AFSS, we saw significant improvements in episode frequency, episode duration,
episode severity and obviously the total AFSS score.These are not only statistically significant.What makes this clinically meaningful is
that you'll see that there's at least a 10 point improvement in each of those
categories in the AFSS.

The
less specific SF-36 domains also showed improvement.We saw improvement in six out of the eight categories.Particularly striking here are the
improvements in role physical, vitality and social functioning.As I mentioned earlier in my presentation,
these were the ones that were more significantly depressed compared to U.S.
norms at the beginning of the study.

The
FDA definition of major complications for catheter ablation studies is an
adverse event that occurs within seven days following an investigational
procedure and is life-threatening, results in permanent impairment or damage to
a body structure, requires significant intervention to prevent permanent
impairment, requires hospitalization or an extended hospital stay, results in
moderate transient impairment or damage to a body structure or requires
intervention such as medication or cardioversion to prevent permanent
impairment or damage to a body structure.This definition was used for our safety analysis.

Using
this definition there were four major complications out of 123 procedures for a
rate of 3.3 percent.There was one
pericardial effusion requiring a pericardial window one week after ablation,
one sinus note injury requiring pacemaker implantation, one stroke occurring
four days after ablation and one AV fistula.

In
the FDA review that will follow our presentation, one additional patient is
coded as a complication who received a pacemaker within seven days.This patient had however pre-existing
documented sinus node dysfunction.Pacemakers as an issue will be addressed later in my presentation.The main point of this slide is to show what
the complications were.You can
appreciate that this is very similar to what's reported in other studies of
radio-frequency ablation.

Adverse
events were tracked beyond the one week mark.In later follow-up, there were 30 patients reporting adverse
events.Six patients had undergone AV
ablation and pacemaker implantation.Two had undergone cardioversion.There were two infections reporting.One was an upper respiratory infection and the other a urinary tract
infection.There was one report of
sinus node dysfunction.There was one
stroke that occurred over a year after the ablation procedure and 41 others who
are detailed in the next slide.

This
is an accounting of all the other adverse events that were reported.Without going into detail of these, most of
these are unlikely to be due to the ablation procedure.The one that caught our attention was the
one patient who had pulmonary hypertension.Looking into this further, this was a patient who had congestive heart
failure and mitro regurgitation.Mild
pulmonary hypertension was detected by an echocardiogram six months after the
ablation procedure.The procedure as
you know is entirely confined to the right atrium and we do not feel that this
was related to the procedure.

Importantly
there were no reports of mortality, cardiac perforation, arterial injury,
stroke or thromboembolism.In fact, 75
percent of the patients reported no adverse events whatsoever.

Having
presented the main data, the main clinical results, I would like now to move to
some other issues for further clarification.The first is the catheters used in the lesion sets.The second is the issue of patients
receiving pacemakers.The third is the
protocol definition of clinical success and the use of antiarrhythmic
drugs.The last is compliance with
transtelephonic monitoring.

The
first issue has mainly to do with thecreation of the isthmus lesion or the flutter line.You will remember that some patients entered
the study after having had a flutter line before. They had a prior
flutter ablation.The anatomy of the
isthmus became better appreciated through the conduct of the study.

Now
we know that it's not a smooth structure, that it has peaks and valleys, the
eustachian ridge.Because of this
complex structure, investigators did not feel that they could always get an
adequate lesion using the REVELATION_ Tx.Because of that, they resorted to standard four millimeterhot tip catheters to complete the flutter
line.

Importantly
the REVELATION_ Tx was used for all non-isthmus linear lesions.The REVELATION_ Tx was used for some of the
isthmus lesions and at the investigators' discretion, they moved to a four
millimeter hot-tip catheter to complete the flutter line.

Because
of this issue, Cardima developed the NavAblator for use in Phase III
specifically to complete flutter line.Despite its introductions, some investigators preferred to use the four
millimeter hot tip catheter that they were accustomed to.Given the fact that flutter ablation is
standard in the AP community, we did not feel that this variation in catheters
used at this location materially affect the results of this study.

Next
issue is pacemakers.The study protocol
stated "Subjects electing to receive implantable pacemakers prior to six
months follow-up will be considered failures."The intent of this statement was that pacemakers should not used
as adjunctive therapy for atrial fibrillation.As I'll show you, most study subjects receiving pacemakers don't fall
into this category.Also as mentioned
at the beginning, patients with pacemakers were not excluded from entering this
study.

A
total of 20 pacemakers were implanted during follow-up.Seven of these were implanted after six
months of follow-up and these do not affect six month efficacy outcomes.Thirteen occurred within six months.Of these, six were for pre-existing sick
sinus syndrome or standard sinus bardycardia indication.

One
was for sinus node injury. This was already reported in major
complications.Another one was for AV
block and not sustained ventricular tachycardia both of which were attributable
to the antiarrhythmic medication that the patient was on.Five others underwent AV node ablation and
pacemaker implementation.

One
had moved away from the study center and at the second center underwent flutter
ablation and then moved on to AV node ablation and pacemaker
implementation.One had changed
insurance coverage and the new physician recommended AV node ablation and
pacemaker implementation. The other three were accounted as treatment
failures in our analysis.

We
looked especially carefully at patients receiving pacemakers within 10 days of
the procedure.There were three such
cases.There was no AV node injury in
any of them.All three had known
pre-existing sinus node dysfunction.Patient one had a heart rate of 49 when in sinus rhythm.Patient two had sinus pauses.Patient three had sinus bardycardia and
three second pauses.We do not think
that these were major complications.They had pacemakers implanted for standard indications.

Interestingly
what we did see was that there was episode reduction in these patients.In patient two for instances there were 34
episodes per month at baseline.This
was reduced to one episode at six months.Patient three had a reduction from six episodes per month to one episode
at six months.

I
would like to deal with the issue of the protocol definition of clinical
success in antiarrhythmic drugs.Consistent with clinical practice, antiarrhythmic medications were
adjusted by the investigator as clinically indicated.The primary clinical endpoint of the study was a reduction in
systematic atrial fibrillation frequency independent of the antiarrhythmic drug
use.As you've already seen this was
achieved in 69 of 81 or 85 percent.We
feel that this is a clinically meaningful endpoint since after addressing the
stroke risk the major issue with atrial fibrillation are the symptoms.

The
study population as you will remember was drug refractory.It was one of the entry criteria.What we found was that there were refractory
to on average three medications.They
had concomitant medical conditions as we've seen.

Clinical
success as defined by the protocol was "a reduction in sAF episodes while
being maintained on the same antiarrhythmic drug regimen or on a reduced
dosage."As determined by the
clinical site, 19 of the 69 successful patients had an increase in
antiarrhythmic drugs.If you take these
19 out of 69 what you are left with is 50 of 81 or 62 percent achieving the
clinical success per this definition.

We
analyzed the antiarrhythmic drugs in more detail. Given the current
information on the efficacy of antiarrhythmic drugs, it is difficult to
determine a true increase in antiarrhythmic drug regimen.

Once
again to go back to who we are dealing with, we started with the 81 evaluable
patients.Fifty percent or at least 75
percent reduction of AF episodes were achieved in 69 or 85 percent.Of these, 50 achieved this with a decrease
or no change in antiarrhythmic drugs for 62 percent.

Antiarrhythmic
drugs are a complicated issue.We
sought to understand this further by doing subsequent analyses.What we did was we first recognized
amiodarone to be in a special category among antiarrhythmic medications.

Dr.
Kay already showed you some efficacy data which distinguishes amiodarone from
other drugs. We grouped class Ia, Ic and Class III into membrane active
drugs.Then the final category was rate
control drugs or no drugs.

What
you can see through the study is that there is a trend towards decreasing
antiarrhythmic medications.Eighteen
patients started on amiodarone.Sixteen
finished on amiodarone.These weren't
necessarily the same patients.Nine
patients were able to discontinue amiodarone.Seven patients started amiodarone through the study.

On
membrane active drugs, there was a trend towards decrease going from 49 at the
beginning to 44 at the end.There was
an increase in patients who were either on no drugs or rate control drugs only
going from 14 to 21 through the study.

We
did a similar analysis for patients who were deemed to be successes based on a
reduction of systematic atrial fibrillation episodes.In here, you'll see that a similar trend.Amiodarone was being taken by 15 patients at
the beginning and 15 patients at the end.There was a decrease in membrane active drugs going from 42 at baseline
to 35 at six months.The number of
patients on either no drugs or rate control drugs only increased from 12 to 19.

This
is the 21 patients who the study sites determined to be an increase.We looked carefully at these.When you look at the numbers, the use of
antiarrhythmic drugs was virtually the same from baseline to six months.Only two of these patients started
amiodarone.

Again
looking at these 21 with the increased antiarrhythmic drugs as coded by the
study center, 19 of these were successful based on the reduction in systematic
atrial fibrillation episodes.Ten of
these 19 had 100 percent reduction.In
other words, they had no atrial fibrillation episodes at six months.The increases in some of these cases were
restarting a drug which was refractory at baseline prior to entering the
study.The other nine had the requisite
at least 50 percent or 75 percent reduction in systematic atrial fibrillation
episodes.

This
is another analysis looking at reaching the primary endpoint versus either a
decrease, no change or an increase in antiarrhythmicdrugs.As you can see,
there is no statistical difference.In
all of these groups, there was 80 to 90 percent success rate.

So
in summary the patients in the study were refractory to an average of three
antiarrhythmicdrugs prior to
enrollment.Interpretation of
antiarrhythmic drug change as you've seen is complex.Antiarrhythmic drug use decreased or remained the same in most of
the patients.Among those with an
increase in antiarrhythmic drugs, very few were placed on amiodarone.Even in those patients with an increase in
antiarrhythmic drugs, the marked reduction in atrial fibrillation episodes is
likely to be due to the procedure rather than due to the changes in
medications.

The
next issue is transtelephonic event monitoring.We had redundant mechanisms in the protocol for capturing episode
data looking for assessment of treatment effect.The first was transtelephonic event monitoring to capture both
spontaneous and scheduled transmissions.The second was office visits where arrhythmia events were reported and
case report forms filed.This included
a clinical history at baseline, one month, three months, six months and 12
months to document atrial fibrillation frequency and severity.EKGs were obtained at these office visits at
baseline, one month, three months and six months.In addition, patients completed an AFSS questionnaire which
provided additional documentation of atrial fibrillation frequency and
severity.

Specifically
on transtelephonic event monitoring the instructions given to the patients were
to record and transmit each systematic episode.In order to make sure that we weren't missing episodes, we also
asked them to transmit at least weekly.They were instructed to perform this at baseline, one month, three
months and six months post ablation.

The
patients were blinded to the required number of AF episodes to enroll in the
study.The transtelephonic monitoring
strips were reviewed by an independent cardiologist to verify a sufficient
number of atrial fibrillation episodes for study eligibility.

There
was an issue of more than one transmission coming in on the same day.We wanted to make sure that these were
discrete episodes.We did the analysis
in a couple of different ways.The
first was to use a constraint of no more than one AF episodes per hour.Under this constraint, all the patients
would have qualified and the six months success rate would be unaffected.If we restricted it further to say that they
could only have one episode of atrial fibrillation on a given day using this
severe constraint, 79 of 81 patients would still have qualified for the
study.So I don't think there's a
question of not having enough episodes.

The
other side line is that most of these patients can tell when their atrial
fibrillation episodes start and stop.So if they recorded more than once in a day, it was usually from
discrete episodes.

This
is a look at transtelephonic event monitoring looking at the number of
transmissions per month first.At
baseline there were 15.5 transmissions. At six months there were 3.9.The second line is shown graphically in the next slide but out of the
transmissions at baseline, 57 percent actually represented atrial fibrillation.At six months of the transmissions, 29
percent showed atrial fibrillation.As
we've already seen, there was a reduction in systematic atrial fibrillation
episodes going from nine per month at baseline to 1.3 per month at the six
month mark.

We
noted that 22 subjects did not transmit recordings at six months.We looked at these as being non-compliant
patients.However these were patients
who were compliant with EKGs and office visits at six months follow-up as well
as with AFSS and that data that will be shown shortly.

But
first on the transmissions that were received, the left bars show the number of
transmissions per month both at baseline and six months.

The
right bars in the darker blue show the percent of transmissions that
represented atrial fibrillation.We've
already seen that there was a drop in transmission rate from baseline to six
months.What's important is that of the
transmissions that were received a still lower percent actually showed atrial
fibrillation at the six month start which speaks to a treatment effect from the
ablation procedure.

The
other mechanisms for capturing the data in patients who weren't transmitting
where the arrhythmia symptoms, the EKGs and the AFSS questionnaire.This was completed by most of the patients.Ninety-nine percent were compliant with
office visits.Ninety-nine percent had
EKGs done at six months.Ninety-one
percent had completed the AFSS questionnaire.

We
continued the analysis of patients who did transmit versus did not
transmit.This is looking at the AFSS
mean scores at six months looking at patients who did transmit in the light
blue versus those who did not transmit.As you can see, there is no significant difference in the two groups
with respect to quality of life.

This
was analyzed further breaking the groups down into patients who transmitted
three or more transmissions at six months versus less than that amount.Once again there was no significant
difference in the AFSS domains between the two groups.

So
to summarize the issues for clarification, the catheters and lesion sets deal
primarily with the lesion at the flutter line.Flutter ablation does not cure atrial fibrillation.Since the adequacy of the flutter line was
something that the investigator had to be comfortable with, different catheters
were used.Since this is a standard
procedure, we did not feel that the use of different catheters at this location
affects the study results.

The
second issue was pacemakers.We looked
at this as first a safety issue and determined that there was only one patient
who received a pacemaker as a complication.The others were generally for standard indications.Of course the patients who received
pacemakers in conjunction with an AV node ablation were considered as failures
by our study, but in the end we don't think that patients receiving pacemakers
as part of this clinical generally affects either safety or effectiveness
endpoints.

The
third issue was the protocol definition of clinical success.This was part of the initial study
protocol.However, we feel that the
primary endpoint is meaningful by itself where the systematic AF reduction is
meaningful clinically.Even looking at
clinical success as defined, this was achieved in 62 percent of the
patients.That's still pretty good.

We
looked specifically at antiarrhythmicdrug use and analyzed it in different ways because it is such a complex
issue.What we saw at the end was there
was a general trend towards drug reduction.Patients were on an average of 1.9 antiarrhythmic drugs at the beginning
and ended with 1.5.For this study
sample size, there was a statistically significant decrease.Once again we feel that the success that we are
seeing is due to the ablation procedure and not due to the changes in
antiarrhythmic drugs.

The
last issue was transtelephonic monitoring compliance.The question here is whether we were unable to capture episode
data.I think you've seen that because
of the redundant mechanisms that were in place that the episode data was
captured and there were significant improvements seen.

Just
once again to highlight the results of the study, the primary endpoint which is
the reduction of AF episodes at six months was achieved in 69 out of 81 or 85
percent.Patients having no atrial
fibrillation at six months numbered 44 of 81 of 54 percent.

The
protocol definition of clinical success which brings in antiarrhythmic drug use
was achieved in 50 of 81 or 62 percent.Thirty-six of the patients had a reduction in antiarrhythmic drugs
through the study, 44 percent.Six
patients or seven percent were off antiarrhythmic drugs by the end of the
study.You have already seen the
quality of life data.There were
significant improvements in several categories.

On
safety, there was no mortality for zero percent.Major complications occurred in four for a rate of three percent.

So
in summary I think what we are seeing here is that the use of REVELATION_ Tx to
deliver right atrial linear relation to address drug refractory systematic
atrial fibrillation is first safe and reasonably effective.Thank you very much.

CHAIRMAN
LASKEY:Thank you.You had originally requested some additional
time.

MS.
WOOD:You originally indicated your
presentation would take an hour.We've
now exceeded that.I would urge you to
try to wrap the presentation up as soon as possible.

DR.
KAY:Thank you.If I could just have a couple of minutes to
do that.Let me just say that as this
study was being performed I must say I was skeptical that the right atrial
ablation would be effective to treat atrial fibrillation.Let me point out that really this is the
first multi-center clinical trial of catheter ablation for atrial fibrillation
to have been completed.

If
you look at it, they met all the prespecified criteria.I think the results show that this is
reasonably successful.It's a moderate
degree of success.It does improve
quality of life.It had a surprisingly
high reduction in the frequency of systematic episodes.It was accomplished with a very low risk of
serious side effects.I think that's
important.

Also
if you look at the centers that did it, it was done at centers across the
spectrum of medical centers and experience.If you look at the risk benefit ratio, remember this is a right sided
procedure that's going to be I think widely applicable.It's a relatively simple procedure.The risks are extremely low especially when
they decided to cut out that anterior line.It's going to be widely applicable to physicians who don't really feel
comfortable going to the left side.

I
think it's likely that this simple right atrial ablation procedure will be
offered to patients who have highly symptomatic paroxysmal atrial
fibrillation.Remember these are people
that had failed a mean of 3 drugs.They
had to fail at least two.It was done
very safely.I think this will be done
as a first line therapy for patients who fail drug therapy before considering
any kind of a more invasive left sided procedure.

This
is the indication the sponsor is requesting which is that it's indicated for
the treatment of atrial fibrillation in patients that are drug refractory with
paroxysmal atrial fibrillation.After
looking at this and looking at it for the holes, it's very robust data.I think that the results in my firm opinion
are that the results from this study provide reasonable assurance that this
REVELATION_ Tx system is both safe and effective for this intended use.Thank you very much.

CHAIRMAN
LASKEY:Thank you.An excellent presentation.Before we move to the short break, I wanted
to ask the panel participants if there were any questions that you wanted to
ask the sponsor before we get to the substantive issues.

As
a non-electrophysiologist, I had one.These patients who are highly prone to atrial fibrillation by selection,
what was the Cumidin program prior to selection for the study?Then how did you handle it post ablation?

DR.
KOCHERIL:That is a good question but
unfortunately that's one where I don't have numbers at my fingertips to give
you.The general scheme though was that
Cumidin was recommended for all these patients.The Cumidin was not discontinued at the end of the
procedure.What we are looking at is a
fairly short window of six months so it's too early to tell whether there would
be sufficient remodeling or other factors to reduce stroke risk.The quick answer without giving you detailed
numbers is that it wasn't changed.

CHAIRMAN
LASKEY:I guess a corollary to that I
can assume that since the TEE was done in close proximity to the procedures so
you didn't identify any atrial thrombi.

DR.
KOCHERIL:No.Exactly, if an atrial thrombus was identified, they wouldn't have
entered for the ablation procedure.

DR.
SCHWARTZMAN:Abe, before you sit down,
a couple of questions.One is practical
or procedural and the other is a clinical endpoint.With respect to the procedure, you mentioned the need for
multiple passes to create a given lesion.The problem with multi-electrode ablation when we started was single
pass.The difficulty obviously is
topography, contact, etc.Can you
elaborate on that?Indeed the procedure
times speak I think apart from the duration of getting the flutter line done
and those who had trouble to the difficulty in creating a linear lesion even
with a multi-electrode catheter.Would
you elaborate on this issue as to the number of passes?What are we actually doing with
multi-electrode catheters to construct a linear lesion?

DR.
KOCHERIL:Sure.A very good question.In order to ensure an adequate linear
lesion, the eight electrodes or several of them at least need to be making
contact with each pass.The ideal
situation would be that the catheter would be placed against the one of the
walls of the atrium and all eight electrodes would make contact.You would deliver an adequate linear lesion
using that segment.

Even
with that especially in the posterior lateral area, you would need to move the
catheter at least once to make sure that the lesion reaches from SVC to
IVC.So even in the perfect setting,
there would generally be two passes to make sure that the linear lesion is
contiguous and adequate.

In
the other areas, there is more difficulty in creating that linear lesion.Typically at the septum you could get a pass
where you enter the atrium from below and are able to advance the catheter
straight and have it sit on the septum.More usually, not all eight will make contact during that pass.Once again it's up to the investigator to
keep track of which electrodes are making contact and where the lesion has been
delivered and then move the catheter up or down to make sure that once again
you haveanatomical obstacle to
anatomical obstacle lesion formation.

What
I do personally in many of these cases if the straight line approach doesn't
work is to come back with a curve on the catheter to make a loop.The advantage there is that if you have a
loop on the catheter you are able to push it up against the atrial wall and
have better contact and more assured contact.That would lessen the procedure time because you'd have more adequate
lesions with the electrodes that are making contact and there would be fewer
passes required to make the lesion.

I
think it is important to make adequate lesions.This was something that was stressed as your investigators were
coming on board.I think we've had
success as a result of accomplishing that.

DR.
SCHWARTZMAN:I presume the vast
majority of investigators were limited to fluoroscopy for guiding catheter
position.

DR.
KOCHERIL:Limited in?

DR.
SCHWARTZMAN:In terms of their ability
to visualize where they actually were relative to the endpoint.

DR.
KOCHERIL:Yes, at the beginning of the
study all there was was fluoroscopy.In
later stages especially in Phase III, a number of the investigators had
acquired non-contact mapping systems.A
couple of the investigators were actually confirming lines using CARDO.

I
think the most common scenario was that investigators got the SI system and
they were confirming conduction block after each linear lesion using the SI
system.But that was not a systematic
part of the protocol.The only
requirement was fluoroscopy which has its limitations.

In
my own hands, I'd had been using Loca lessa just to see that there aren't
significant gaps that we can track a linear lesion in a crude way using that
system.But different techniques were
employed later in the study but that was not part of the study design.

DR.
SCHWARTZMAN:With respect to that, can
you comment as you know the ability of local electrogram quality amplitude
fractionation to act as an indicator of contiguity, continuity or whatever you
want call linear lesions whether or not that is a relevant, desirable
endpoint?That is the stated endpoint
in this study based on your own experience of your collaborators with more
traditional conduction based assessment of complete block.What are your thoughts as to what you get
from this technology?

DR.
KOCHERIL:Another very good
question.As you know, this isn't the
only catheter system to look at that as an endpoint.I was involved in the Thermocool catheter study recently.That was one of the stated ways of knowing
that an adequate lesion was being delivered.So it is used and it is a standard of sorts within the AP
community.However what you are raising
as the question is how do you know that it's an adequate lesion after seeing
that.

Quite
frankly we don't know.I think the big
picture here is that we got good results.We got symptomatic AF episode reduction and I think we were doing some
good.The animal data is very
helpful.It shows that adequate
transmural contiguous lesions can be delivered with this catheter system
employed in the fashion we were using it in the clinical trial.But aside from telling you that that was
what was looked for, there's no good way to confirm that it confirms an
adequate lesion.

DR.
KAY:I just want to make two comments
to that question.When the study was
designed, the question was do you have to confirm these linear lesions.The point you bring up are right on target,
David, in terms of it's hard to even make a flutter line in patients.That can take two or three hours
particularly with standard catheters when you really have to confirm that it's
complete and linear.

The
strategy that was employed in this clinical trial was that we take this floppy
catheter.We draw these linear lesions.
We don't confirm anything.A part
of the protocol was not confirming that the lesions were continuous or anchored
or that there was electrical block or anything because as soon as you throw
that in, it becomes an incredibly complex procedure.It adds another three or four hours of time to do the
mapping.It marries the system to some
complex mapping system.

The
strategy was you take this catheter.You draw these lines based on these electrogram markers that yes, you've
created a lesion.That's the only
evidence that you have that the lesion has been created.

I
think what was striking when you used this catheter is you burn with this
catheter and the electrograms really disappear.You really have very good confidence that you've created a
lesion.Are they all complete?No.Are they all transmural?No.Are they all anchored?No.But the strategy was you put these lines in in this position and here
are the results.Does that help reduce
the atrial fibrillation burden in atrial fibrillation?That's an important aspect of the
protocol.It was a strategy rather than
the science of linear lesion creation and these other things.

DR.
WALDO:This is Al Waldo.Can I make a comment here too because I too
was concerned about the definitions of block.I think anybody who looks at that would be very skeptical.The only one that is a definition of block
is the double potentials what you called "split potentials."

It
seemed to me that was what was used for a measure of procedural success.Now you are saying that it wasn't.Is that the idea that ?- signal only means self-conduction in most
instances while amplitude signals don't mean there's no conduction?I was wondering why those endpoints were
chosen but were not used.

DR.
KAY:Al, your points are on
target.Clearly the endpoint of the
study was not creation of three linear lesions with demonstration of complete
block across each one of these linear lesions.The objective of the study was to deliver lesions in certain
trajectories using this catheter and to have some measure that you've created a
lesion which a reduction of amplitude of the electrogram and so forth but not
that you've definitely completed a transmural, complete linear lesion that has
no gaps in it.

So
your question is a good one and I think that speaks to this as a strategy.The strategy was not to have complete
contiguous lesions but to deliver lesions.As far as split potentials, many times you see split electrograms.
Sometimes you just see a reduction of the electrogram amplitude but I
think you can always be quite confident that you would able to deliver a lesion
that had some measure of the fact that a lesion was created at a given
location.

DR.
WALDO:I think that says delivery of
the lesion is there but the notion that you obtained block is not demonstrated
in my opinion.Now the other thing I
would ask is since this was a totally empiric approach, would you review again
with us or would someone review with us again why you selected these sites to
do it?Then as a correlate to that, do
you know that you needed all those sites?It's so empiric in the first place but a little more about that would
help me.

DR.
KAY:Again a very good point.When the study was designed, the question
was where should these lesions be.Do
we have any notion? The only data that at least I'm aware of is the Cox
Maze procedure they have flutter line and then a cava line.About the time the study was designed there
was a number of reports.

You
probably remember Michelle Hassenger's paper that was on the cover of "The
Journal of Cardiovascular AP" showing atrial fibrillation terminating
during a burn with a right atrial lesions that was again a inner cava line and
that had a lateral line compartmentalized in the atrium in a horizontal
direction.Everyone had a slightly
different lesion set.

So
the question is which of these is the most critical lesion.We don't know.It's like in the Cox Maze procedure.We don't know which one of those lesions is critical.There has now been some work subtracting
some of them and the results seem to decrease the more you subtract.Once this type of technology gets approved
and available, investigators can do substudies looking at peeling lesions away
and seeing if you just do a inner cava line and a flutter line do you get the
same results as if you put in all three lines.

So
I guess the answer is we don't know.This was the best guess that the folks that designed the lesions, Jeremy
Rusk and David Keane, looking at the literature available in 1996.But it is an empiric approach.

DR.
WALDO:I think that's important, Hugh,
because as you well know with beginning to find out about mechanism of atrial
fibrillation most of the time it looks like there's some kind of drive and most
often it's on the left side.The
original Maze operation as everyone well knows was designed to treat multiple ?- which don't appear to be very often in the
mechanism of atrial fibrillation.The
striking data that was pointed to of the Maze procedure shows thatless is as good or better.The interesting thing about the Maze
operation is that it doesn't make any distinction between paroxysmal and
persistent or even permanent atrial fibrillation.So all these empiric approaches I find that it's hard to know how
to evaluate them.Where and why to put
lesions is an issue still.

DR.
KAY:Yes, I think the other point which
you make is the surgeons have a difficult time because once you do a
thorocotomy you have one time in to get the job done.You're not going to bring patients back for redo procedures.One of the things that the electrophysiology
community has an opportunity to now as new tools become available is to start
looking at this more critically and trying to figure out what lesion sets are
better in a procedure that you do as an out-patient procedure from the leg
rather than from a thorocotomy.

But
all your questions are terrific.I
think as a scientist studying reentry, this empiric approach probably goes
against your general grain in its fact that we aren't proving this and proving
that.But this is a clinical strategy
that we are looking at today.

DR.
WALDO:As a clinician, it does too I
might tell you.There are some other
questions as well if I can follow up.We heard no mention at all about a weight control.Of course, weight control is a very
important part of symptoms and you are dealing with symptomatic atrial
fibrillation.Are there any data you
can give us about how carefully this is looked at and what impact this may have
had on assessment of the whole picture here?

DR.
KAY:Certainly in weight control
anddrugs, patients were managed by the
clinical investigators, how they usually would be managed so that rate control
could go up or could go down during the course of the study.As we looked at the fine studies if they
switched from Cardizim to Verapamil or Cardizim to a beta-blocker, it's hard to
say again what's up or down or a lateral move.

If
Digoxin is stopped, is that a decrease?If Digoxin is added, is that an increase?If you switch from Verapamil and abeta-blocker to just the beta-blocker at a higher dose, is that
an increase?Is that a decrease?I think what we basically came away with is
that it's very hard to say that they are up or they are down.So that's how we ended up with these broad
groups of amiodarone going up on drug therapy.Amiodarone stoppings are going down on drug therapy.I think everyone would agree on that.

Then
having these broader classes of membrane active drugs versus rate control drugs
in most patients had a general decrease in drug therapy whether they were going
off amiodarone or off membrane active drugs or the same or decrease rate
control drugs.But it is very difficult
as you get into these dose questions. Then you have concomitant
hypertension and other issues that a patient is being treated for.

DR.
WALDO:Let me be more specific.Were there any criteria for maintaining
adequate rate control?For instances if
you decided that when your patients returned, you wanted their rate less than
80 for any number of reasons, they might not be symptomatic.Whereas if you didn't have such good control
and may recur at a ventricular rate of 120, they would be symptomatic.It might be that you could have missed lots
of episodes because someone was taking good care of the rate control.Do you have any data or anything you can
enlighten us on this aspect of the study?

DR.
KAY:Well the study design was
thatantiarrhythmic drugs or drugs
related to atrial fibrillation would be kept unchanged.So that was the study design.The study design was not to do the ablation
and then double rate control drugs and see how they do.The study design was that antiarrhythmic
therapy or therapy for atrial fibrillation was maintained during the course of
the study.

The
protocol did not specify decrease or increase in any way.What we see in all studies is physicians
manage patients as they think is best for the patients.So we saw some motion as I mentioned in
calcium blockers, beta blockers.Then
how do you interpret that?It becomes
very difficult as you look at each patient through a microscope. But
overall I believe looking at the data that I've seen that there was overall no
change in the rate control strategies that were used.

DR.
WALDO:Thank you.

DR.
SCHWARTZMAN:I wonder if I might follow
up on where Dr. Waldo was going which was characterizing burden.Having been involved with studies like this,
I can empathize that it's extremely difficult short of an implantable full
encompassing holder recorder to get to the nitty-gritty here.

Nevertheless
I think what's well established is that based on the context of the study is
support involved, psychosocial issues patients naturally characterize lower
burdens after intervention than before.I'm not criticizing the design of the study.Without a placebo or parallel arm, I don't think that was
possible.But nevertheless I need a
better understanding of burden not in relation to symptoms as much as what was
happening electrocardiographically.

So
two specific questions.One is it's
unclear to me that patients were complying post ablation with these weekly
mandatory transtelephonic monitoring issues.Can you give me a little better flavor whether they were complying?I just don't understand.If so, what the data showed asymptomatic,
just routine weekly recordings which as I understand it was part of the
protocol?

The
second question is there was a high rate of electro 12 lead EKGs at
follow-up.Can you give us any data as
to what the atrial rhythm was at those times?

DR.
KAY:As far as the study, it was
designed on this whole issue about how do you measure atrial fibrillation
burden.It was very challenging other
than this continuous 24 hour Holter which would make your skin fall off or put
in the Reveals (PH) but they can't even detect atrial fibrillation with much
accuracy.So it's a very difficult
question.

The
way this study was designed was to do it the best they could possibly think.
So what did they do?One had an
outside company in charge of it.So it
wasn't something that was in-house.It
was an outside event monitoring who was in charge.

Each
patient when they went home was asked to give a day that was the best day that
they were supposed to transmit.So they
may say Monday.They may say Wednesday.They may say Friday.Every week they are supposed to transmit
whether they are in sinus rhythm or not.They are just supposed to transmit their rhythm.

What
we found is over time, that compliance with that decreased.By six months, I think 20 of the patients
transmitted never even though they were supposed to transmit every week.
They transmitted none.What the
event monitoring company was to do not if they don't transmit just do nothing
but really go after the data.They
would call the patient.If the patient
didn't transmit on Monday which is their day, they would call the patient on
Tuesday and say "Could you please try to transmit".They would get on the telephone or leave a
message.

When
they got through, the patients would say "Well I'm feeling just fine and
I'm not having fib so I didn't transmit."They really struggled to try to get very good compliance but what they
found is what we see.If a patient has
the procedure today,six months later
they are feeling and if someone is calling them and telling them to start
transmitting these episodes for no benefit to them, then they just have a hard
time motivating themselves to do it.

I
think that accounts for the fact that there was less than perfect compliance
which speaks to this notion that we need some implantable monitor to do this in
future to make it an easier job.I
think a heroic effort was taken.All
this is documented.The event monitor
documents.We called X patient on this
day and the patient said that they are doing fine and they didn't want to
transmit.These are in the logs from
this event monitoring company.

As
far as the EKGs, these patients did show up to their six month appointment and
said that their quality of life was better.They are doing fine.They aren't
having an atrial fibrillation and the EKGs were obtained which showed almost
uniformly sinus rhythm.There were
sample patients that showed atrial fibrillation at that six month follow-up
point but that was five to ten percent, a very small number.Most of them were feeling good.They are having no atrial fibrillation.They are in sinus rhythm on 1280 EKG at the
six month follow-up point.

I
was encouraged by the fact that these weren't patients ?- The skeptic would say that all these patients
were on amiodarone at the end.Well,
that's obviously not the case.The
skeptic would say that these patients have no benefits so they just disappear
and didn't complete the study.They did
complete the study.They showed up to
their visit.They told people they were
feeling fine and not having any atrial fibrillation and the EKG largely showed
no atrial fibrillation.

Those
that did transmit a lower frequency were atrial fibrillation so there's lots of
things speaking to that.But it also
speaks to the fact that it's very hard to get this perfect compliance in
patients largely who are active, patients that have lives and jobs to do and
things like that.

DR.
SCHWARTZMAN:This issue of reduction of
symptoms associated with atypical AF management floating around whether that's
due to psychosocial factors or better rate controls Dr. Waldo mentions or even
anesthetization for lack of a better term based on collateral damage to cardiac
enervation, can you comment on whether there was some undercurrent observed in
your cohort along the lines of a reduction in per event symptom burden or is it
just too much of a vague science?

DR.
KAY:I think it is a vague
science.I think one of the questions
which the community has been thinking about this is why is this catheter that's
just doing a right atrial approach seeming to have such really striking benefit
to these patients.The mechanisms that
have been proposed are either reentry rotors that are in the right atrium.Even though most in the left atrium, there
are some in theright atrium.

There's
a recent paper presented by Ashian Chen looking at rotors near the SVC.So the fact that two of the lines are
anchored to the SVC may have taken care of rotors going around the SVC or
perhaps even triggers in the SVC.Sonny
Jackman likes the notion of autonomic function and maybe somehow this is
affecting the autonomics.

We
don't have a clear understanding of exactly what is the mechanism of benefit
and of the lines which is the critical line.I think we feel quite confident that it's not the flutter line
becausewe know you do flutter
ablations and what do you see in the follow-up but atrial fibrillation.
But all weknow is this lesion
and you get these results.

As
far as the per episode symptoms at least in my own group of patients, it seemed
like when they had atrial fibrillation these patients tend to know it and they
tend to transmit the episodes.There
was really fairly good correlation.In
the beginning prior to the ablation, only half the episodes show atrial
fibrillation even when the patient thought they had atrial fibrillation.

But
as time went by, even less showed atrial fibrillation.So these patients were highly tuned into
their heart rhythm, would transmit and would show premature atrial beats.I remember in many of our patients we would
get these transmissions come through and they show APBs.The patient may have thought they were in
atrial fibrillation but they were in sinus with APBs.I think it's a very tough problem to wrap your hand around well.

DR.
SCHWARTZMAN:You don't think patients
were rendered asymptomatic or minimally symptomatic in regard to their AF by
the ablation procedure.

DR.
KAY:Yes, I do not get the impression
that patients were now in atrial fibrillation and their symptoms were
gone.They would show up at the six
months follow-up appointment saying that they felt fine.You do an EKG. Even though they felt
fine thought they were in sinus or in atrial fibrillation.I've seen that with some of our pulmonary
vein patients but I did not see that with our center's patients that were in
the study.

DR.
SCHWARTZMAN:I just have one
housekeeping question.I just want to
understand this issue of increase. The way you presented it made it seem
like you left to the nurse coordinators at each center to characterize what
that meant.That makes me nervous.So for example on slide 100, you show 69
patients with successes, 42 on a membrane active drug.Seven of those patients went to amiodarone
at six months.

Yet
for those characterizing increase, only two of that group of patients from
membrane active went to amiodarone.I
would think all seven would be characterized as an increase of change from Type
I or III or nonamio to amio.I just
want to make sure that I understand how this was done.

DR.
KAY:Let me give my version of this and
then Abe will give his.On the form, it
said in the follow-up is the patient on more or less of the same antiarrhythmic
drugs.Did the patient have an
increase?That was really independent
of the company.That was the
investigator that coordinated to check that box or not.To agree that it's completely out of any
post hoc analysis, we can't go back in now and change it.They checked the box the way they thought
the box was supposed to be checked.That's what we have.

What
we found as you get in and look at it some of the times they would say it's an
increase because you went from amiodarone to flecainide and a beta-blocker.So the number increased but you went off of
amiodarone.So that's why we looked at
it again as far as these broad groups which we thought were as an
electrophysiologist when I looked at the data this is something that everyone
could understand.You start the
amio.That's more.You stop the amio.That's less.There were
some patients that went from Sotolal 80 BID to Sotolal 160 once a day.It seems funny to give it once a day but is
that an increase or a decrease.The
dose is up.The frequency is down.It just becomes difficult.Let me give it back to Abe.

DR.
KOCHERIL:Dave, you were astute to pick
up who was filling out that information.It was supposed to be determined by the study site and very often it did
flow to the study coordinator to do that.As Hugh illustrated, this is very complex in determining exactly what
happened. That's why we redid the analysis breaking it up into
amiodarone, membrane active drugs and rate control drugs because that's easier
for the EP community to understand.I
think that basically looks good from our standpoint.

The
issues were just as Hugh outlinedwhat
was coded as increases.If there was an
increase in some fashion, there was one patient who was on both flecainide and
amiodarone at baseline.Flecainide dose
was increased.The amiodarone was
discontinued.Yet that patient was
counted as an increase.

These
issues of doses going up and down even in some of the patients who received
amiodarone and would legitimately be considered by all of us in EP to be
increase, a couple of those patients were actual refractory to amiodarone at
baseline and then did well on it afterwards.

So
yes, it was an increase in medications but that speaks to a treatment effect if
it was refractory at baseline and they responded later.But it is a complex issue.We analyzed it in multiple different ways
because it is such a complex issue.In
our final analyses breaking it up into amiodarone versus membrane active versus
rate control, the overall trend is to decrease medications during the study.

CHAIRMAN
LASKEY:And the panelists will have
additional time for query.

DR.
WALDO:This is Al Waldo.Can I ask a couple of other questions now?

CHAIRMAN
LASKEY:Al, how about one question and
then we'll break.

DR.
WALDO:One point and then one
question.Very brief.Hugh was saying that the A2 front isthmus
lesion doesn't affect atrial fibrillation.The data from Walling lab showed 15 percent of cases were affected that
way.They speculated a rotor that involves
the flutter isthmus.So I think there
are data that that lesion may have some effect.

The
thing I wanted to get to is what were the overall number of patients on
amiodarone.The reason I ask that is it
gets back to one of my earlier points about rate control.Amiodarone is an excellent AV nodal blocking
agent.I still have some concerns about
symptoms and rate control and how you assess burden.I would like to know really what percentage of the 81 patients
that you were dealing that were analyzable were on amiodarone.

DR.
KAY:Eighteen patients started on
amiodarone and 16 ended up on amiodarone.That decreased.As far as the
flutter line, I think your point is correct although I don't think that's major
effect of this protocol.Certainly for
pulmonary vein isolation, very few centers do a flutter line as part of that
procedure.Clearly all we know is that
these three lines together decrease symptomatic atrial fibrillation
episodes.The line that we have
actually confirmed conduction block is the flutter line.

DR.
WALDO:But you are making that point
though and that is requisite in most instances that you need antiarrhythmic
drug therapy.Isn't that right?

DR.
KAY:Yes, most the patients. Only
six patients were off all drugs and 21 patients were off any membrane active or
amiodarone drugs.That would be 59
patients were still on antiarrhythmic agents at the end of the study.

CHAIRMAN
LASKEY:I'll take advantage of this
pregnant pause to break and let's meet back in 15 minutes.I have 11:20 a.m. so 11:35 a.m. we'll have
the FDA presentation.Thank you.Off the record.

(Whereupon,
the foregoing matter went off the record at 11:22 a.m. and went back on the
record at 11:42 a.m.)

CHAIRMAN
LASKEY:Back on the record.Thank you all.Prior to continuing with the FDA presentation, Ms. Wood had an
announcement.

MS.
WOOD:I need to make a point of
clarification.Dr. Thomas Ferguson was
read in the voting status statement in error this morning.He is not participating in today's meeting.Also I would like to once again remind the
speakers that when they come up to the podium to speak although you have
previously introduced yourselves for the benefit of the transcriptionist,
please identify yourself once again before you begin speaking.Thank you.

CHAIRMAN
LASKEY:And now may we have the FDA.
Thank you. Welcome.

MS.
DEMIAN:Thank you.Good morning.My name is Cindy Demian and I'm the FDA Lead Reviewer for the
Cardima REVELATION_ Tx Microcatheter with NavAblatorTM RF Ablation
System submitted under PMA P020039.The
FDA presentation will provide an overview of the following: identify the FDA
review team members; provide a brief overview of the Agency's interactions with
Cardima; provide a brief summary of the description of the products; discuss
the non-clinical evaluation and summarize the major outstanding device
performance issues to date; provide a summary of the clinical and statistical
evaluationand conclusions; and
identify the FDA questions for the panel.

The
FDA team was comprised of myself, our medical officer, Dr. Lesley Ewing, who
will present the FDA clinical review summary, our statistician, Dr. Heng Li,
who will present the FDA statistical review summary, Dr. Nick Jensen, who
performed the animal review, James Cheng, who performed the electrical
engineering review, Lisa Kennell, who performed the sterilization review and
Barbara Crowl, who performedthe
bioresearch monitoring review.

The
sponsor proposed the following indications in their PMA application as well as
in their panel pack.It is worth noting
that this indication mentions creating a set of continuous linear lesions along
the lateral and septal walls and along the isthmus in the right atrium.However the sponsor has chosen to use the
shorter version which you see here which mentions ablating with a set of
continuous linear lesions in the right atrium.

I
would like to briefly discuss the history of the Agency's interactions with
Cardima.In December 1997, the
sponsor's feasibility study was approved which included 10 patients.

Then
in July 1998, FDA Advisory Committee made recommendations for atrial
fibrillation clinical study designs.In
particular they recommended a single arm study where the patient serves as
their own control.This Advisory
Committee recommended a 75 percent decrease in the frequency of symptomatic
episodes or cure as considered as clinically significant endpoints in the
treatment of atrial fibrillation.

In
August 1998, the sponsor submitted their first progress report on their first
five patients.However there were
problems with creating the isthmus line with the REVELATION_ Tx.The FDA recommended that Cardima could
either pursue a licensing agreement with another company for use of an approved
standard four millimeter ablation catheter or Cardima could design their own
catheter in order to complete the procedure.Cardima opted to design their own standard four millimeter
catheter.In addition the Agency
informed Cardima that the use of non-investigational device would be considered
a clinical failure.

A
few months later, in December 1998, the sponsor submitted their progress report
from the next five patients, now a total of 10.However despite the FDA's concerns, there was still wide spread
use of non-investigational catheters in Cardima's study.

Then
two years later in May 2000, Cardima was granted approval to begin their
pivotal trial, Phase III.In addition
the NavAblatorTM 4mm catheter was added to their IDE.At that time, the Agency's thinking was that
80 patients would be treated with the new catheter and there would be
sufficient acute and chronic effectiveness results within a narrow enough
confidence interval to properly evaluate the NavAblatorTM.Again FDA continued to communicate to the
sponsor that the use of non-investigational catheters were considered failures.

Then
in June 2000, the sponsor met with the Agency where the company agreed and
stated in their meeting minutes that they do not want to pool the feasibility
with the pivotal.

A
year later in May 2001 Cardima submitted a progress report on their Phase IIb
patients.FDA informed Cardima of our
concerns which were primarily based on the feasibility results.The first concern was that there was patient
non-compliance with transtelephonic monitoring.The second concern was that there was varying definitions of
acute success.

The
basic components of the RF Ablation System are the catheters, the accessories
and a compatible RF generator.In
particular, the catheters include the REVELATION_ Tx Micro Ablation Catheter
and the NavAblatorTM 4mm Ablation Catheter.The accessories consist of the NaviportTM
Guiding Catheter, the REVELATIONTM Tx Select Switch Box and the
REVELATIONTM Tx Cables.Investigational generators were used in this clinical study.However it is worth noting that a compatible
generator is needed in order to properly function with the Cardima catheters.

Specifically
the REVELATION_ Tx Microcatheter is a 3.7 French single use catheter.It is steerable and has non-deflectable
distal tip coil.It's flexible and has
non-electrically active tip.It has
eight electrodes and eight thermocouple temperature sensors on the distal end
of the catheter.The ablation
electrodes are 6 mm in length and it has a 90/10 platinum iridium tip.Radio frequency is applied to each
individual electrode to produce thin linear RF ablation lines.This catheter is used with a deflectable
guiding catheter, the NaviportTM, to properly position the distal
tip.

The
NavAblatorTM is an 8 French 4mm ablation, single use, catheter.It has an electrically active deflectable
tip.It has four electrodes including
one embedded in its tip just proximal to the thermocouple.This catheter is intended to create spot
lesions from its tip and is designed to be used without a guiding
catheter.This catheter has a control
mechanism in the handle that activates a pull wire to steer and deflect the tip
which can be locked in place when the desired curve or position has been
achieved.

The
NaviportTM Guiding Catheter is used to aid in the positioning of the
REVELATIONTM Tx.This
guiding catheter is sterile, single use catheter that has a dual lumen, a
device lumen and closed pull wire lumen.This device has already been cleared through the 510(k) process for the
same intended use.However it is
integral to the REVELATION_ Ablation System and so it is described here as an
accessory.

This
catheter has a deflecting mechanism that allows for its tip to be straighten
while be inserted into and while it's deflected into the heart.It also features a friction locking
mechanism that permits the distal tip to retain its deflected shape once the
catheter is in position for ablation.

FDA's
preclinical review goals were safety and reliability. The safety was to
ensure that the device has been appropriately designed and tested and that the
safety features have been qualified for use.The second preclinical review goal was reliability which was to ensure
that the device design and manufacturer provides assurance of consistency with
performance of the catheters.

The
Catheter Preclinical Qualifications included biocompatibility testing of
catheter materials, reliability of the catheter design, mechanical and
electrical testing of the catheter performance and qualification of the
sterilization procedures.

The
Preclinical Conclusions are as follows.Preclinical testing performed by the sponsor is designed appropriately
and met the pre-specified pass/fail criteria.In addition, testing shows that the device can be reliably manufactured
to meet the product specifications.

It
is important to note however that there were several device failures for the
REVELATION_ Tx catheter that occurred in this clinical trial that were not
predicted by the clinical testing.We
are working with the sponsor to determine how these failures will be
mitigated.I would like to mention that
the customer experience reports do not discuss all of the issues in
detail.However there are a few points
that are worth noting.

For
example, there were five complaints in which the Coagulum formed on
electrodes.There were seven complaints
of rough burrs or in which there was delamination of THV which is a coating to
improve the conductivity of the electrodes.

In
addition, there were 21 electrical failures which included thermocouples and
electrodes.Specific examples of
electrical failure complaints included such comments as "the thermocouples
never registered temperature".There were complaints of electrodes in specified positions not ablating.There were noisy ECG signals.There were complaints of electrode noise or
cross talk.

In
addition, there were also three complaints regarding failure of the cable which
is an accessory to the Cardima system.These cable failures are not included in this table.This concludes the preclinical
evaluation.Dr. Lesley Ewing will now
present the clinical summary portion of this presentation.

DR.
EWING:Good morning.I am Lesley Ewing and I do not have any
financial conflicts to report.As
you've heard the Indications for Use statement that Cardima proposed for the
clinical trial included treatment of the patient with paroxysmal atrial
fibrillation and using a set of linear lesions along the lateral and septal
walls and along the isthmus.This is
the indication upon which the clinical trial was based.

As
you also have heard, the Cardima catheter system is composed of two
catheters.TheREVELATION_ Tx which in the proposed
indication for use in the PMA states that it's "intended for the creation
of continuous liner lesions for the purpose of interrupting arrhythmia
pathways."The NavAblatorTM
was to be used when the REVELATION_ Tx was not used to complete the isthmus
lesion.

It
was a single arm, non-randomized study which began in 1997. There were
three study phases.The submission of
the PMA includes data from Phases IIb and III. The major difference
between the lattertwo stages was the
introduction of a new catheter to the device system.

The
inclusion and exclusion criteria have been presented by the sponsor.

The
patients underwent a baseline pre-ablation monitoring period during which 30
days prior to the ablation they were to achieve a minimum of three episodes of
symptomatic paroxysmal atrial fibrillation to be eligible for ablation.It is the FDA's information that the
patients were aware thata minimum
number of episodes were required.Re-screening was allowed and for re-screening the patients if they did
not meet the initial baseline screening period they were required to have a
total of nine episodes over 90 days, so three episodes per 30 days.

The
ablation procedure has been described and as specified by the protocol, it
includes three linear lesions: the posterolateral, the posteroseptal and the
tricuspid isthmus. The anterior lesion was optional.According to the protocol, all lesions were
to be attempted first by the REVELATION_ Tx catheter.If the tricuspid isthmus lesion was not successful, then the
NavAblatorTM catheter could be used.

The
follow-up was at one, three, six, 12 and 24 months. The 24 month
follow-up was by telephone.There are
quality of life questionnaires at three and six months.Those were compared to the baseline quality
of life questionnaires.The patients
were given a transtelephonic monitor which was used up to six months.As has been previously discussed, the
transmissions were to be compulsory weekly during the first, third and sixth
month even if the patient was without symptoms.

The
primary effectiveness endpoint was reduction in frequency of symptomatic
episodes during the sixth month for a thirty time period post ablation
procedure compared to the baseline period while on the same medications or
reduced dosage.Because the endpoint
was to be measured during this discrete sixth month post ablation period, the
Agency thinks that it is important to try to standardize medication use.

If
the patients had five or more episodes in the baseline period, they were called
successful if they had 50 percent less episodes during that sixth month post
ablation.If they had three or four
episodes, they were required to have 75 percent decrease.That worked out to be that if they had three
episodes in their baseline period, they were required to have zero episodes to
be called a success.The episodes were
to be counted by a measurement of if it was truly atrial fibrillation on their
transtelephonic monitor.

The
secondary endpoint was improvement in the quality of life.

The
procedural success endpoint was as also has been discussed the demonstration of
one of the following at lines of ablation during sinus rhythm:reduction in amplitude; fragmentation or
widening of local electrograms; split potentials; orincrease in pacing threshold.Prior to Phase III, the pivotal trial, the increase in pacing threshold
was required by the study protocol but that requirement was dropped in Phase
III to measure the increase in pacing threshold.

The
safety endpoint was incidence of complications.Major complications were for 7 days and adverse events in the 24
months post ablation.

There
were 120 patients that had the procedure performed and there were 116 that had
verified data.The demographics I will
not go over because the sponsor has gone over these.

The
mean procedure time was 250 minutes plus or minus 123 minutes.The range was 100 to 755 minutes.Mean fluoroscopy time was 47 plus or minus
46 minutes with a range of two minutes to 265 minutes.

As
you will hear for the rest of my slides, there are numbers from the FDA review
which are slightly different from what the sponsor has reported.I will describe why those numbers are
different.But also in an attempt to be
transparentin the Appendix to the FDA
clinical review, the data upon which the review team made these decisions is
presented and available to verify the numbers one way or the other.

As
I said there was 120 patients that had the linear ablation procedure and 116
patients had verified data which Cardima presented to the FDA.There were five patients that when the
independent cardiologist reviewed the transtelephonic monitoring, there was a
dispute upon the number of atrial fibrillation episodes.Those patients are not included in the
effectiveness cohort per the FDA.

So
there were 111 patients that had unambiguous number of baseline episodes.Out of that 111 patients, there were 21
patients that had less than six months follow-up.Two were deemed lost to follow-up and the Agency's number of
effectiveness cohort is 88.The
patients that left the study or went on to have a further procedure to treat
atrial fibrillation are included in this number of 88.

So
the denominator for safety for the adverse events is 116 patients and the
effectiveness cohort is 88 patients.

The
number of atrial fibrillation episodes at baseline is shown in this table and
has been discussed.It also has been
mentioned that there is a range of accuracy of whether the patient actually was
having atrial fibrillation when they transmitted symptomatic episodes.On this graph you can see number of patients
on the vertical axis and the horizontal axis is the percentage of the
transmissions that actually were symptomatic atrial fibrillation.

There
is a wide range of this.The percentage
of symptomatic transmissions that were ultimately diagnosed to be atrial
fibrillation ranged from 12.9 to 100 percent.It is also unknown whether each transmission represented a discrete
atrial fibrillation episode.

I
do have available for the panel's review if requested the actual logs from the
symptomatic transmissions.The sponsor
submitted detailed information on 89 patients.There were 62 of these patients that transmitted multiple times per day
on at least one day of the 30 days.Five patients had atrial fibrillation transmissions within five
minutes.Seven patients had atrial
fibrillation transmission at least twice within 30 minutes.Twenty-six of these patients had
transmissions twice between one and three hours.

In
terms of the ablation procedure that was actually performed, not all of the
patients had the same lesion set performed.The REVELATION_ Tx catheter, the microcatheter, was used for all septal
and lateral linear lesions.Some
patients had only a non-investigational catheter used for the tricuspid isthmus
lesion.The non-investigational
catheters used were from five different manufacturers and included a cooled tip
catheter.

As
you can see from this chart, the majority of patients, 82 percent, did have the
standard protocol defined linear lesion set.But there are a number who did not.

This
chart shows the breakdown of the different catheters that were used for this
procedure.In Phase IIb, the NavAblatorTM
was not available to the investigators but you can see that of the patients who
received a tricuspid isthmus lesion, 21 out of the 33 had the REVELATION_ Tx
catheter used first.But 12 had a
non-investigational catheter used. So the investigational catheter plus a
non-investigational device was used.

In
Phase III when the NavAblatorTM was available, the REVELATION_ Tx
was used first for the tricuspid isthmus lesion in only eight patients.And the NavAblatorTM was tried
first in 57.But eight patients
continued to have an non-investigational catheter used instead of the
investigational device system.As I
said, this is just the description of the patients that had a tricuspid isthmus
lesion.The other lesions were
attempted with the REVELATION_ Tx.

So
the protocol was that the REVELATION_ Tx was to be used for all lesions and the
NavAblatorTM was to be used if the REVELATION_ Tx was unsuccessful
to the tricuspid isthmus lesion.The
NavAblatorTM was used in 59 out of the 116 patients.In 57 out of 59 of those times, it was the
first catheter to be used at the isthmus.In 10 of those patients, a non-investigational catheter was also
required in addition to first attempting the lesion with the NavAblatorTM.

In
measurement of the successful biodirectional conduction block at the tricuspid
isthmus using the NavAblatorTM catheter, there were 42 out of 59
patients who were successful with the first use of the NavAblatorTM.In comparison, the non-investigational
catheters used alone at the tricuspid isthmus were successful 100 percent of
the time achieved bidirectional conduction block.

And
as has been previously discussed, the sponsor states that there is not adequate
information available to measure acute procedural success.

In
addition to this being an endpoint for the study, the other issue that has been
raised is when does the electrophysiologist know that the lesion has been successfully
completed.We do not have information
to tell the FDA upon what decision point the individual investigator used to
stop their lesion.So some
investigators may have used a different criteria than others and the procedure
for the use of the investigational catheter might be slightly different per
procedure.

In
the transtelephonic monitoring in the sixth month post procedure, information
submitted by the sponsor included detailed information on 83 patients.Out of these 83 patients, there are 22
patients who had no transmissions.We
do know that at least two of these patients either lost the monitor or had a
non-functioning monitor. There are 31 additional patients that
transmitted between one and three times.So 53 out of the patients upon which we have information had poor
compliance with monitoring in the six month post procedure.

To
chart the number of patients that actually did achieve the primary
effectiveness endpoint, there were 88 patients in the effectiveness
cohort.As previously stated, 70 of
those patients had the lesions performed only with Cardima catheters primarily.

There
were 18 patients that had the Cardima catheter plus a non-investigational
catheter used.In other words, the
non-investigational catheter was used primarily for the isthmus lesion.The lesion were only done with Cardima
catheters in 70 patients and 58 of those ?- Actually
this slide after going over these slides so many times.The lesions done with primarily Cardima
catheters and non-investigational catheters secondarily. So there were 58
patients who had only Cardima catheters, 12 patients that used both but only
after using the Cardima catheter first.

Out
of the patients who only used Cardima catheters, there were 24 who reached
primary effectiveness, 34 who did not.Out of the patients who had Cardima catheters first and did
non-investigational catheters secondarily, there were seven who reached the
primary effectiveness and five who did not.Then of the patients who had the non-investigational catheter used
primarily for the tricuspid lesion, there were 11 who reached primary
effectiveness and seven who did not.

To
look at this in a slightly different way, there were 42 out of the whole 88
patients who were in the effectiveness cohort who reached the primary
effectiveness endpoint and that is the reduction and symptomatic episodes that
meets the prespecified endpoint during the sixth month post ablation compared
to baseline while all on the same medications or reduced dosage.

Out
of those 42 patients that meet the primary effectiveness endpoint, 24 reached
the primary effectiveness endpoint using only the investigational device
system.Out of that 42, there were 18
patients who required a non-investigational catheter to complete the ablation
procedure.The breakdown of that 18
patients is seven used the non-investigational catheter secondarily after using
a Cardima catheter and 11 who used the non-investigational device primarily.

Of
the patients that were deemed to have failed the primary endpoint, eight had AV
node ablation prior to the sixth month.Five had a pacemaker prior to the sixth month which is a prespecified
failure according to the protocol.One
withdrew due to failure to improve.Nine did not have sufficient episode reduction.Twenty-one did have episode reduction but
with a new antiarrhythmic drug or increased dose.This also includes two patients who also had a pacemaker
implantation.Two patients had both an
increase in antiarrhythmic drug and an insufficient reduction in episodes.

There
were 43 out of the 88 patient effectiveness cohort that were reported no events
or transmitted no events in the sixth month post ablation.Two of this 43 have had an AV node ablation,
one prior to the sixth month and one after the sixth month assessment.One out of the 43 had a surgical MAZE
procedure after the sixth month assessment time period.One out of this group had an atrial
defibrillator after the sixth month assessment period.Seven of these patients had amiodarone added
prior to the sixth month assessment.

In
terms of antiarrhythmic drugs that the patients were taking in the sixth month,
there were data presented on 82 patients.This data is included as I had mentioned before in the appendix to the
clinical review.There were 14 patients
that were on no antiarrhythmic drugs or no Class I or Class III.Six of these patients also were on the same
medication regime that they were at baseline.So eight patients had changed.

There
were 26 patients that had an increase in their antiarrhythmic drug dosage or an
adding of an antiarrhythmic drug.Amiodarone was added in six and removed in 10.

There
were 10 patients out of the effectiveness cohort of 88 that had an AV node
ablation procedure the linear percutaneous ablation procedure.Two patients went on to have a surgical MAZE
after the linear percutaneous ablation procedure.

The
secondary effectiveness endpoint for the study was improvement in quality of
life as measured by the Short Form-36 and the Atrium Fibrillation Severity
Scale compared to baseline.

When
the patients were compared to their baseline and in the sixth month assessment
period, there were greater than 50 percent that had a clinically significant
improvement only in the vitality domain of the SF-36 but in two domains of the
AFSS.This information does include all
of the patients that had disputed baseline numbers and it includes some
patients who had an AV node ablation.

The
patients who had major complications within seven days of the ablation procedure
includes patients that have been described already by the sponsor.But the Agency has included one additional
patient as the sponsor had mentioned.This patient is the fourth patient down that had sinus node dysfunction
and required pacing within three days of the procedure.

This
patient is included in the Agency's assessment of adverse events because the
patient required emergent or semi-emergent transcutaneous or transvenous
pacing.The documentation says both.Because of the urgency of the treatment
required and also it was not a planned pacemaker even if the patient had sinus
node dysfunction, it was somewhat unexpected to the investigators that the
patient needed to have a pacemaker implanted.

According
to the strict definition of major complications as has been presented by the
sponsor, the two other patients that had pacemaker implantation in the week
post ablation procedure really would fit into the definition.This is an issue that we are hoping that the
panel will discuss because it is in this study without a control group.It can be difficult in this patient
population to know if these are truly adverse events or not.

So
five out of 116 patients or 4.3 percent with a confidence interval of 1.7 and
9.4 percent of the patients had one or more major complications.Also a possible safety concern is the 20
patients that a requirement for a pacemaker implantation in the follow-up
period of the study which ranged from one day to 1.5 years after ablation.There were seven patients that had pacemaker
implanted within six months of the ablation procedure without an AV node
ablation.

Dr.
Li will present the statistical summary and then I will come back to the podium
and present the summary statements of the presentation.

DR.
LI:As Dr. Ewing has mentioned, the
study is a single arm, non-randomized, multi-center study with subjects serving
as their own controls which means that the treatment effect is primarily
evaluated by comparing the post treatment measurements to its corresponding
pretreatment measurements.

Unlike
many of the investigational protocols for IDEs, this particular one didn't come
with an explicitly stated rule that specifies what the study results have to be
in order for the investigational device system to be approved.

But
data still are looking for interpretation in relation to safety and
effectiveness.So I will make some
remarks that may be relevant to such interpretation.My comments will consist of some general remarks about this kind
of study which I will refer to as single arm, pre/post study in general and how
they might apply to this particular study.It will include an issue that is very special to this study under
discussion.

Every
design comes with a standard list of pitfalls that are routinely
contemplated.This study is no
exception.By pitfalls I mean the
existence of factors that are not separable from the treatment effect.That is to say when study outcomes may be
considered to be explained by the treatment effect not being zero, it can also
be explained by those factors.

For
this particular kind of study mainlysingle arm, pre/post study, there are some general pitfalls.I will go over those items one by one.History means that some events may happen
between pretreatment measurement and post-treatment measurement, events such as
the approval of a new drug.

Second
there may be changes within subjects themselves.One thing that inevitably changes is the age so that's probably
how the name "maturation" is given to this kind of pitfall.

Third
is placebo effect which is the effect of the perception of treatment instead of
the treatment itself.Those endpoints
that are subjective self-evaluations may be considered to be particular
vulnerable to placebo effect but few endpoints are known to be immune to the
influence of such an artifact.

Fourth
is selection.The way that patients are
selected along may influence the distribution of the post-treatment measurement
in relation to its corresponding pretreatment measurement.

Here
are some of these pitfalls that may apply to this particular study.Placebo effect.The secondary endpoint is clearly a subjective
self-evaluation.And to some extent,
the primary endpoint may also be considered as subjective to the extent that
it's self administered.

Maturation.The subjects may experience some changes in
the interim between the pretreatmentmeasurement and the post-treatment measurement in terms of motivation to
report events and as has been mentioned there is possibility that a single
episode may mistakenly be recorded as a multiple episode.So the ability to avoid such mistakes may
also change as the subjects are getting familiar with this procedure.A so-called learning curve.

Selection.As we know, patients are selected according
to their AF frequency during a 30 day screening period.As we know, some patients may typically have
three or more episodes per a 30 day period.Some people may just be caught in a bad month and for the second kind of
patients, their frequency of episodes may go down post-treatment.Some may refer to this as a "regression
to the mean" effect.

The
above issues are general to the kind of study which is called single arm,
pre/post.Here is a very special issue
to the current study under discussion.As we know, the study procedures were performed using
non-investigational devices on a sizable number of study subjects.Those subjects are not randomly selected
which means that the patients who are treated only with investigational devices
do not form a random subgroup of all the study subjects.

How
this statement is supportive of the statistical aspect of the conclusion which
Dr. Ewing will present shortly is logically fairly straight forward. So
instead of belaboring the point in strictly statistical terms, I'm going to use
a metaphor.

Imagine
a picture being cut into two pieces and one of the pieces is lost.You are presented with the remaining
picture.The question is do we know or
do we have any information of what the original whole picture would look like when
the lost piece was found.You would
immediately ask what kind of picture and how were the pieces cut.In general, the question has no answer.

Suppose
someone comes and presents you with a piece from another picture and the
question is would this additional piece help you figure out what the original
picture looked like. The answer in general would be perhaps "No, it
wouldn't be that helpful."

In
this metaphor, the missing piece refers to the outcomes that would have
observed for those patients treated with non-investigational devices had they
been treated with investigational devices only.The remaining piece of this picture refers to the data on those
patients who were actually treated with the investigational devices only.The piece from another picture refers to
those patients who were actually treated with non-investigational devices.With that, I'll turn the podium back to Dr.
Ewing.

DR.
EWING:Some summation statements that
the FDA would like to leave you with were that:

1.The ablation procedure, the lesion made and
catheters used, was not the same for all the patients in the study.(a) There were a variety of investigational
and non-investigational catheters used for one of the lesions.(b) A small number, 38 out of 116 or 33
percent, of the patients had the ablation procedure performed using the
investigational device system as specified by the protocol. That is all
of the lesions to be performed first with REVELATION_ Tx catheter.(c) Some patients did not have the lesion
set performed as specified by the protocol.

2.As a result of the unblinded study design,
there could be a bias toward reporting AF episodes at baseline and against
reporting in the sixth month.

3.Acute procedural success cannot be assessed
for the procedures in the study due to incomplete reporting of the various
acute procedural endpoints.

4.Some patients had further procedures to
treat paroxysmal atrial fibrillation after the linear ablation procedure.

5.Twenty patients had a pacemaker implanted
one day to 1.5 years post procedure.

6.There was poor compliance with
"compulsory" transtelephonic monitoring during the sixth month.

7.More than 50 percent of the patients had
clinically significant improvement in two AFSS domains.The quality of life results include data
from patients with the ambiguous number of baseline episodes and some patients
who had an AV node ablation procedure.

So
in conclusion from the clinical and statistical perspective, it is not clear if
data can support any conclusion about the safety and effectiveness of the
investigational device system.

CHAIRMAN
LASKEY:Thank you, FDA.We have some time again from the panel to
query the FDA on some elements of their presentation.

DR.
NORMAND:Can you see me?I don't know if you can see my hand going
up.It's really important for me to
understand some of the numbers in the very first table because some mention has
been made of that fact that a sizable number of the participants had
non-investigational devices.I just
look at the numbers and I keep getting different numbers.Can you just go over it one more time, the
table where you're saying that X number of patients had non-investigational
devices just to help me understand it a little bit better.

DR.
EWING:Okay.This table?

DR.
NORMAND:Yes, that table.

DR.
EWING:There is a difference in some of
the numbers.I based these numbers on
the information that was presented in Table A-19 which is included in the
appendix.This table is my counting of
the numbers.

DR.
NORMAND:So if you can just tell me
what your table means.Is it the
"other only" that are the non-investigational?

DR.
EWING:The "other" is the
non-investigational.

DR.
NORMAND:So 20 out of 108 are not
non-investigational in the FDA's opinion.

DR.
EWING:Correct.It's definitely non-protocol devices.Then there were also non-investigational
devices used after the Cardima catheter was tried and we assume it failed to
produce the lesion that the investigator thought.So it's a combination of non-investigational catheters which were
used first or after the Cardima catheter failed.

DR.
NORMAND:That would be the 20 plus the
eight plus the 10?

DR.
EWING:Correct.

DR.
NORMAND:In other words, anything with
"other" in it.I'm being
simplistic.

DR.
EWING:Correct.

DR.
NORMAND:Thank you.

DR.
EWING:Should I sit?

DR.
GILLIAM:No, I have one question.In your review, was the "other"
catheters used to make a line any other place other than only the isthmus line?

DR.
EWING:No, only the tricuspid
isthmusline.

DR.
GILLIAM:Okay.

DR.
TRACY:Warren, can I ask her a
question?This is a huge difference of
effectiveness from 85 to 47 percent.Did you look at including the "other" when there was another
catheter used?What would your
effectiveness have been if you were calculating?

DR.
EWING:That is actually the total
number of patients that reached the primary effectiveness point which is 42 out
of 88.That included patients who had
only the Cardima catheter used and who had the Cardima plus a
non-investigational catheter used.

DR.
TRACY:Can you explain again why are
your numbers so different?I'm lost.

DR.
EWING:From Cardima?

DR.
TRACY:Yes.

DR.
EWING:We included the patients that
went on to have another procedure such as AV node ablation if they perceived
the linear ablation procedure failed.So the patients that the sponsor called "withdrawn", we
included in the effectiveness endpoint.

That's
part of the answer but the other answer is that they included patients that had
a pacemaker implanted as successes.According to the protocol, patients who had a pacemaker implanted before
the six months were to be called failures.We called them failures.There
are seven patients included in the increased antiarrhythmic drug group that
were different from the sponsor's mainly because they added or increased
amiodarone.

But
you are right.Our numbers are
different than the sponsor's and as I said before that`s why I included the
data upon which I made these decisions in the panel pack.

CHAIRMAN
LASKEY:But in no instance were these
issues prespecified?Your
definition?Their definition?No drug manipulation for example.

DR.
EWING:There was not a prespecified
protocol for antiarrhythmic drug use.

CHAIRMAN
LASKEY:Which in term ties into success
by your definition.

DR.
EWING:Correct.

CHAIRMAN
LASKEY:So that was not hashed out in
the deliberations leading up to the conduct of the protocol.

DR.
EWING:Actually I don't know what was
discussed but it was not included in the protocol.Just because it is not in the protocol does not mean it was not
discussed with the Agency.

CHAIRMAN
LASKEY:It's just helpful to us.

DR.
EWING:The honest answer is I don't
know that it was discussed.

CHAIRMAN
LASKEY:We have some of the history but
obviously we don't have all of the history.Any other questions from the panel?

DR.
SCHWARTZMAN:Being new to this side of
the table, I don't know if this is cricket because beyond what's being asked of
the company, but I wonder if some of the clinicians might comment on whatever
one year experience they have.Certainly from a clinical point of view, six months is almost no time.One year is very short.

What
we really want is multi-year data particularly given the fact that these are
relatively young patients.It is
obviously in the context of trying to get approval it's not possible.But I imagine given the timing of this study
there was substantial one year experience.I wonder if any of the clinicians might comment on whether these
patients have maintained a stable program which is hybrid therapy, ablation
plus whatever drug they are on, early post- or pre- at one year.

DR.
KOCHERIL:Abe Kocheril.Dave, I can give you a couple of different
answers to that question.My overall
experience with this type of catheter system goes back to the REVELATION_
catheter which preceded the Tx.I had
published a study using that off label to deliver linear lesions for paroxysmal
atrial fibrillation.This was published
in the journal of "Interventional Cardiac Electrophysiology."

That
reported on 29 patients who had the procedure done and the follow-up time at
the end of data collection was 19.7 months.So it's almost two years.There
was significant reduction in AF episodes.Actually this was more of a rigorous look.Seventy-nine percent were free of AF and off medications at the
mean follow-up of 19.7 months.

I'm
not sure that we have enough data to answer it from the Phase III clinical or
even combining Phase IIb and III.There
are patients who have completed the one year time point and a few who have
completed the two year time point.But
I don't think they have enough numbers to say that for sure.

My
experience consists of the 29 that were published.I have probably a total experience of 50 using the REVELATION_
catheter.Then I've enrolled 20 some
odd patients in Phase III.The overall
experience has been positive but that's a very good point.That's a short window of observation.

DR.
KAY:There was one thing that I wanted
to help clarify.That is this numbers
problem that Cindy brought up as far as why the numbers are so different.I think there are two things.One is theway Cardima looked at it which is you started with 81 patients and how
many met the bar as far as reduction in symptomatic atrial fibrillation
episodes at 50 or 75 percent.

The
primary endpoint in the study which is specified in the protocol is reduction
in symptomatic atrial fibrillation episodes.A secondary endpoint is clinical efficacy which has to do with the drug
effects.So the primary endpoint that
we spoke about was 85 percent of patients had a 50 or 75 percent reduction in
symptomatic atrial fibrillation episodes not looking at the antiarrhythmic drug
motion during the study.

Once
you factor that in at least as identified by the investigators that's where our
numbers drop down to a 62 percent efficacy.Then as we look at the drugs, it's very hard to figure this motion of
drugs up and down. But when we look at
the picture of the big circles, we saw a motion down and not a motion up.That's the main point that we wanted to
make.

CHAIRMAN
LASKEY:Yes, we're actually trying to
confine our comments to the Agency but thank you for the elaboration.Again just to remind all of us, we really
need to confine our thinking to the material at hand.While the other long term stuff is of interest, we can only judge
what's here in the panel pack today.If
not, I suggest that we break for lunch and resume in one hour at 1:30 p.m.Thank you.Off the record.

(Whereupon,
at 12:39 p.m., the above-entitled matter recessed to reconvene at 1:42 p.m. the
same day.)

A-F-T-E-R-N-O-O-NS-E-S-S-I-O-N

1:42
p.m.

CHAIRMAN
LASKEY:On the record.I'd like to call us back to order.In order to stay on schedule or perhaps even
be ahead of schedule, let's move on with the open committee discussion.I would like to have Dr. Gilliam present his
review please.I'm going to have my
timer on here, Rosie.

DR.
GILLIAM:Well, then I guess I'll have
to move quickly.

CHAIRMAN
LASKEY:Correct.

DR.
GILLIAM:I have a few questions
regarding the investigators first.The
time of ablation of 250 minutes seems long.I know I saw one that was 755 minutes.God help us that day.Is there a
comment on that?This seems a pretty
straight forward procedure.What are
the complexities that make this literally a four hour procedure?

DR.
CALKINS:It is interesting looking at
those numbers how long it ends up taking. I think there's a couple of things.One is it's the old question of how long does ablation really
take from when they get on the table to when they leave the table as opposed to
in case of the academic institution when the actual attending shows up to be
there during the burn.The things that
make this procedure less than a 30 minute procedure are (1) the flutter line.Early in the protocol there was a
requirement that you had to try this REVELATION_ catheter for ?- You know isthmuses really are not designed to
be ablated with a linear catheter so that added a considerable amount of time
early on to the procedure.Then (2) it
was using the 4mm catheter to get complete isthmus blocks.

So
there is a certain amount of time goes for a flutter ablation and then you have
two more linear lesions.When you do
ablate along the lateral wall, we'll pace to make sure we don't have any
phrenic nerve stimulations and so forth.Then at very points in the protocol, you had this requirement to record
every electrogram and print things out and measure things so all of that ended
up slowing things down.

If
you say how long does it take to do just to go in without having to do some of
these steps and go straight and use the NavAblatorTM instead of
having to use the REVELATION_ first, I think it's a one to two hour ablation
time procedure and not a three to four.I suspect the 755 minute case was when some of these cases people were
looking out of interest with the ESI system.Was there block and was there not block? As soon as you start throwing in complex mapping systems, you can
add an awful lot of time to our procedure that's not the heart of the essence
of the procedure as I see it.

DR.
GILLIAM:While you're there, another
question concerns me.This isn't your
chart but it's this chart that's on 79 that shows the episode frequency.Do they mean episode frequency starts out at
baseline at 9.2?At three months
afterwards, it's 3.5.At six months
after, it's 1.2.Obviously it didn't do
anything between three months and six months.How do you account for that?

DR.
CALKINS:It was interesting looking at
that slide because it was strikingly how the number of symptomatic atrial
fibrillation episodes seem to decrease over time.Looking at the data the only way I can explain it are two
things.I believe the data.1) You have the whole issue of reverse
remodeling that sinus rhythm begets sinus rhythm.2) I think we're all aware of the fact that you do an atrial
fibrillation ablation whether it's a pulmonary vein ablation or any ablation
and you're getting transmural lesions, you're creating some information that
indicating a healthy phase.

Certainly
in these pulmonary vein isolations, we see it in a very dramatic way that lasts
for one to three months.It can last up
to a fair amount of time, up to three months for this irritability phase.So if you say there's an antiarrhythmic
effect of the procedure that happens immediately, you balance that with some
healing phase inflammation.That gives
you a little more atrial fibrillation early on and then this remodeling to my
mind is how I can explain it over time is atrial fibrillation keeps getting
better and better.Those are the two
things that come to mind to explain this continued improvement in the
symptomatic atrial fibrillation episodes.

DR.
GILLIAM:My concern again was whether
we just got the episodes.Whether
people either became frustrated or they had a placebo effect to the event and
they just either stopped calling in or gave up.That's the one concern I have because I don't know early on given
that the variability of atrial fibrillation from 12 percent to some people are
100 percent as far as knowing whether they are in atrial fibrillation when they
send in their transmissions.Did you
all consider the potential of doing weekly transmissions before the procedure
during that month of time to document what they were doing and then follow up
afterwards?

DR.
CALKINS:Yes, I think how is the best
way to document these atrial fibrillations and quantify it.I think we all struggle with it every
day.Other than David's suggestion
which was a continuous Holter monitor that you have every single day and trade
in, it's basically impossible.I guess
the REVEAL is one option.All these
things were considered.

This
study was designed five years ago.But
even today, you say that event monitors seem to be the best we can do.You say that maybe we should do Holter
monitors periodically.In this study,
patients did transmit weekly pre- and post- to get trained in this routine of
Tuesday is your day for transmitting.

All
I can say is I think this is the best approach we have.By having it in an outside company and the
outside company calling the patient, I think every effort was made to make them
comply.This is just a reality.But then when the patient showed up, they
felt better and they were in sinus rhythm on their EKG.

DR.
GILLIAM:And regarding that, there are
five pacemaker patients I think prior to the procedure.Were any of these patients evaluated using
their pacemaker counters to determine whether they had a decrease in their
atrial fibrillation episodes using the counters before and afterwards?

DR.
CALKINS:I'm not aware of that
data.I don't know if those were Abe's
patients but that's certainly another way to monitor this.But I don't think we have that data.It was not collected as part of the study.

DR.
GILLIAM:That would be obviously a
pretty easy way to see mode switching episodes or even actual documentation of
atrial fibrillation in some way.There
is a question raised and I'm not sure that you have the answer.Potentially some of these patients could
have had the same episode of atrial fibrillation but lasted a longer period of
time.Do you have any take on that?

Could
someone have been in atrial fibrillation for a long period of time to actually
get their three episodes?Was there a
requirement for instance of normal sinus rhythm documentation between episodes
of atrial fibrillation in any way?

DR.
CALKINS:No, I think your point is well
taken.It's amazing now as we look at
all this to say that here's another ten things that retrospectively maybe we
should have done.You could say that
it's clear what happened.The patient
one episode of atrial fibrillation that lasted an hour that transmitted 20
times in the hour and that's your 20 episodes.That's why we are seeing such a good benefit.

We
went back and looked at the data to address the issue saying if you defined
this episode as being separated by at least an hour, the actual time that it
was recorded, what does that do to the numbers and does it effect the affect at
all.If you say that throughout we only
at most will allow one episode per day and separate by days, then you'll only
loss two patients.

Our
interpretation is no, that's not what we were seeing. These were patients
with paroxysmal atrial fibrillation that were in general aware when they were
in or out.But I think that was a valid
concern.When we looked at it I was
relieved to say it wasn't the patients that were cheating the books that they
were transmitting 20 times in an hour and one episode of atrial
fibrillation.These patients all have
multiple atrial fibrillation in multiple days pre- and no atrial fibrillation
documented post or little atrial fibrillation.

DR.
GILLIAM:The selection of
patients.There are 20 centers.Obviously you have a lot more atrial
fibrillation patients than 80 you would think that you would have over the
period of time.Was there any selection
that you spoke with the investigators to see how they selected who would enter
the trial other than just doing the monitoring?

DR.
CALKINS:I think there's a lot of
different centers that were involved in the study.The question is how did a given center find these patients.The reality is you sign up to a clinical
study and you start thinking you're going to have a lot of patients and you
approach patients with this incredibly cumbersome thing.They have to have this event monitor.
They have to transmit for six months. They're going to get called at home
if they don't transmit.They say
"No thanks.Let's just use the
off-label non-thermocouple version of the catheter or the heck with it.Let's skip it."The patients then disappear.

The
other thing we saw during this study in some centers when the study started a
pulmonary vein atrial fibrillation didn't exist.As the study was going along, that showed up.For centers that wanted to be doing the
ultimate novel unknown thing, that was something that people started getting
involved with.So some centers
initially on put in five or ten patients and then they say "The latest
thing is atrial fibrillation of pulmonary veins.I want to be doing that."So the patients would be steered to that so they could build up their
experience with that procedure.

What
we've learned obviously as we look back, four years ago we were ablating deep
into the pulmonary veins creating all this pulmonary vein stenosis thinking we
were doing good.At the end of the day,
a lot of people were stepping back and saying "We have to be out of the
pulmonary veins for that."This
study has just been chugging along coming to completion and showing very sound
data and very excellent safety.

DR.
GILLIAM:Looking at the catheter
itself, I'm not sure that you necessarily need to answer this but I think you
might be able to.It looks as if it's
really difficult to manipulate the tip of the catheter.It needs a delivery system to get it where
you put it.Why is this catheter more
useful than a regular ablation catheter in doing essentially point by point?

DR.
CALKINS:There are a couple of unique
features of the catheter.It's
incredibly flexible and floppy as you can see.That allows it to conform to the heart, move with the beating heart and
so forth.It's delivered with the
Naviport_ catheter so it ends up being a deflectable catheter with this floppy
curve.Sometimes you can get all eight
electrodes in touch with the wall and sometimes only four.Because it's floppy, it's closely adherent.

Then
the question about the lesion characteristics when we worked with the dogs,
these were nice and linear.When you
just try to do a point by point pullback, you get these skips and gaps.Also you're debulking the atrium.You're creating these 5mm marbles every time
you burn with a standard RF catheter.With this, they are 2mm to 3mm thick and they are equally deep.So this is more doing what we are trying to
do which is not ablate the atrium but put roadblocks up to ablate atrial fibrillation.

DR.
GILLIAM:Given that, you would think
that for a flutter line this is almost be a preference rather than the point to
point for almost the same reasons.The
fact that it would conform will allow it to deal with the ridges and the
aggravations that wetypically run into
doing a flutter line.

DR.
CALKINS:The issue there is the
flutter.I saw Anton Becker (PH) had a
presentation at the NASPII (PH) meeting which was just terrific showing the
anatomy of the right atrium and the pecta eight muscles that fan out in the
flora of the flutter isthmus.There's
been many companies that have tried to ablate the isthmus with a linear
catheter and all have failed.

There
hasn't been a single linear catheter system ever tried in humans.In dogs, the dog isthmus is nice and
smooth.It always works.In humans it's these huge pecta eight
muscles and you need to drop down into the valleys with a end tip firing
catheter that's the critical thing.

In
this study early on, people worked with that catheter.We learned you have these pecta eight
muscles.It's the wrong catheter for
that job.You need an end hole
catheter.That's when the NavAblatorTM
came in and then the NavAblatorTM is interchangeable with an 4mm tip
end hole catheter.It's just whatever
you like in terms of the handling characteristics.

DR.
GILLIAM:I have one more question and
then I'll turn it over.I may come back
and ask some more.This question may
not be playing fair but I do need to ask it.When you do your pulmonary vein ablations now, do you routinely do
right-sided lines as these lines would dictate?

DR.
CALKINS:I just isolate the four
pulmonary veins and do a left-sided line, left flutter, left inferior vein.

DR.
GILLIAM:Do you do any right-sided
ablations in addition?

DR.
CALKINS:For redos, we'll bring them
back and we'll isolate the superior vena cava and do a flutter line and so
forth.But we won't for a standard
pulmonary vein case.I think very few
people are.Piroget (PH) and the rest
of them aren't working on the right side routinely for the pulmonary vein
isolation procedures.

DR.
GILLIAM:Thanks.

CHAIRMAN
LASKEY:Great, Rosie.Thank you.Bill.

DR.
MAISEL:Good afternoon.First I would like to congratulate both the
sponsor and the FDA on excellent presentations this morning.I think you really highlighted and clarified
many of the issues that I had certainly.What I would like to do is focus on several areas that I think warrant a
little further discussion and perhaps a little clarification from the sponsor
and the FDA on these issues.

DR.
WALDO:Could you speak a little louder?

DR.
MAISEL:The specific issues that I have
include the procedural methodology including the creation of the lesion sets,
the procedural endpoints and the use of multiple catheters in individual
patients, safety issues with particular attention to the post-procedure
pacemaker implantation rate and then the assessment of the pre- and
post-procedural atrial fibrillation.We
have touched on many of these issues already.

With
regard to the standard lesion set, the sponsor states that the protocol did not
define a standard lesion set and that the optimal lesion set is not identified
by the results of this study nor was it an objective of the protocol.That being said, 83 percent of patients
received the posteroseptal, posterolateral and the isthmus lines.

That
number increases to close to 90 percent if you include the patients who had a
prior isthmus ablation.So in more than
90 percent of the procedures, at least three of the proposed four potential
right atrial lines were made.For me,
while there is variation lesion set that the patients received, it seems
reasonable to group the patients and consider the outcomes of the procedure as
a whole.

More
challenging to me is the interpretation of that procedural endpoints.As we've discussed already, the procedural
success was defined in the protocol as demonstration of at least one of the
following: reduction in the amplitude, fragmentation or widening of the local
electrogram, appearance as split potentials or an increase in the pacing
threshold.

As
noted in FDA reviews, these procedural endpoints were not consistently measured
or recorded on the data forms. The sponsor indicates that no conclusion
can be made regarding the acute procedural success endpoint.I perceive the lack of a clear procedural
endpoint as a problem.I think it makes
it difficult to instruct physicians performing the procedure on how to assess
to the acute success.

So
I would be interested in knowing from the sponsor specifically what are your
instructions to the physicians performing the procedure as to how to perform
the lesions and when is the procedure done.

DR.
KAY:Neal Kay.I'll try to give the best I can.I haven't use this catheter but I've used
others to try to do linear ablations in the right atrium.It's extraordinary challenging.I think that part of these procedure times
that Dr. Gilliam was asking about really are related to trying to figure out
did you get block.I think looking for
double potentials is great if you know the direction of propagation.If it's going parallel with your line, you
may not see any double potentials even though there is block.So it is a challenge.

I
think that right now the state of the art at present is to decrease the
amplitude of the electrogram and then to try to some kind of mapping method to
pace on one side of the line and show block.Just looking back the way this procedure was done, a lot of these
techniques we use now with electroanatomic mapping just were not available when
this procedure came up.

Let
me just also address some of the confusion.I think Dr. Ewing's presentation was outstanding. There is a
question of who do you group and how do you include in this based on what the
flutter line was ablated with.It's
pretty clear that the linear ablation was all done with this REVELATION_
catheter.

DR.
MAISEL:If I could just interrupt.I'm trying to clarify for a physician
performing the procedure what precisely are the instructions to that procedure
about what they should do with the catheter.How long should they be applying RF?Are there temperature guidelines that you recommend?Is there a way for them to know when they
create a lesion that they don't need to reapply RF at that site?Can you just spell those explicitly out so
that we can understand how the procedure will be performed?

DR.
KAY:Let me ask Abe.He actually did the protocol so he can tell
you how long they applied RF for?

DR.
KOCHERIL:Abe Kochenil.I guess before I go into the specific
details.The air has changed so if the
study was being redone today theseelectroanatomic mapping techniques would help in making sure that the
lines were delivered.

What
was done in the protocol was to deliver lesions.There was a thermocouple so we could measure temperature.We would want at least a 10 degree rise over
body temperature to make sure that we were actually doing something to the
tissue.The typical application was a
minute at a time so each electrode gets a minute worth of burn.During the burn, all of us are trained to
look at those electrograms and even with all the caveats we are looking for
those electrograms to shrink and there is an internal assessment of what's
going on.

This
is fairly easily to transmit to an electrophysiologist who wants to pick up the
procedure and that would be the current instruction.It's just to use what we already know to be markers of getting an
adequate lesion.But the guidelines are
to get that temperature and keep it up for a minute.

DR.
MAISEL:Do we have any idea on how many
of the patients or lesion sets met those criteria?I realize we didn't measure threshold and all those things.I'm trying to understand what those are
based on.

DR.
KOCHERIL:This is definitely soft and
that's what you're reacting to.But the
best we have is the investigator assessments and according to that assessment,
110 out of 118 were successful in accomplishing that.

DR.
MAISEL:Okay.Thank you.The next issue
is the use of multiple catheters in individual patients.As I already stated with the exception of
the isthmus lesions, all the right atrial linear lesions were created with the
REVELATION_ Tx catheter.A variety of
catheters were utilized to create the triscuspid isthmus lesions.The numbers vary in different places in the
application but the general message is the same.

The
REVELATION_ Tx catheter was used in 31 patients and of those 10 or almost
one-third required a second catheter for the isthmus.The NavAblatorTM was used in 59 patients and in 10 of
these or one in six an off-protocol catheter was required to achieve
bidirectional isthmus block.

So
in 70 of 108 patients bidirectional block was achieved with only the protocol
catheters although admittedly the NavAblatorTM was not used in some
patients because it was not part of the initial protocol.An overall 84 percent of the patients
achieved bidirectional block.The
success rate of the non-investigational catheter when used alone was 100
percent and was 81 percent when used after another catheter.To me the rate of isthmus block seems a
little lower than I'd expected.I would
be interested in hearing your thoughts about why that might be.

DR.
CALKINS:I appreciate the
question.Hugh Calkins.I think it really comes down to how hard you
try with a given catheter before you switch to a new tool.If you used a tool for three years and you
are used to using whatever manufacturer's catheter that's what you're really
comfortable and that's what you want when things aren't going real quick and
the day is getting long.That's when
you want to go to what you're most familiar with.That's what we faced.

I
firmly believe and there's been animal studies to show that and the company has
data showing that a lesion generated with the NavAblatorTM is
exactly the same as the lesion generated with 4mm catheter made by XYZ Company
and there's absolutely no difference.I
think you and I would both believe that as an electrophysiologist understanding
the principles of RF energy.

It
comes down to handling of the catheter and what you're comfortable with.What we saw was that investigators would ?- The protocol said you had to use the NavAblatorTM.It's not the catheter you really like.You humor this protocol for so long, given
it 10 or 15 minutes.If you don't get
block, you're going to switch to the catheter you have been using longer and
just feel more comfortable with.I
think that's what we saw.

If
you were to do a study where you put me in a room with the two catheter and say
get isthmus block.I think no one gets
100 percent with a 4mm catheter.Some
patients have very thick isthmuses.You
need irrigated catheters or 8mm catheters or something else.So the 100 percent I don't believe either
for the non.But all of us will get
isthmus block in about 90 percent with any 4mm catheter and 50 watts of RF
energy and that's the reality of what we are seeing.It's how long do you try before you switch.

DR.
MAISEL:Thank you.I think the use of multiple catheters
including some off-protocol catheters makes it a little challenging to
interpret the data but you do provide a breakdown of the individual catheters
and success rates.It's in the clinical
summary which I think helps allow for interpretation of isthmus block.

I
would like to move on to some of the safety issues with particular attention to
the post-procedure pacemaker implantation rate.Five of 116 patients per the FDA had major complications within a
week of the procedure.An additional
three patients required pacemakers within two weeks and overall 20 or
approximately 23 percent of patients had pacemakers implanted during the course
of this study, nine of these following AV node ablation.

I
think the issue of post-procedure pacemaker is an important one for several
reasons.For one, there is certainly
data that for patients with sick sinus syndrome pacing the atrium may reduce
the incidence of atrial fibrillation.We all acknowledge that these patients are at higher risk for receiving
pacemakers.They are on multiple
drugs.They have sick sinus syndrome.

The
questions for us are is the procedure associated with a significant risk of
post-procedure pacemaker and if it is, is that increased risk justified by the
important clinical benefit.Some
patients and physicians may be willing to accept a higher risk of pacemaker if
the procedure is successful. Do we have any data maybe historical data
regarding atrial fibrillation patients who are refractory to medications on
multiple drugs and what the expected pacemaker implantation rate might be in
those patients?It just strikes me as a
high number, 23 percent of patients receiving the pacemakers.

DR.
CALKINS:Again Hugh Calkins.I appreciate the question.A couple of things to bring out.One is that the 23 patients we're looking at
data from six months.So from six
months follow-up, 13 patients have pacemakers.So the 20 is adding in pacemakers that had occurred in the second six
months which isn't the data that we are focusing on today.So 13 patients had pacemakers.

I'm
not aware of any comparable data taking patients with paroxysmal atrial
fibrillation refractory to two or more drugs or to amiodarone and seen over six
months of follow-up how many will end with pacemakers.I suspect it's a fair number.

Certainly
while this study was going on, this is the same period where some of the
studies were coming out, the St. Jude, DAO pacing algorithm for atrial
fibrillation.There was a lot of hype
during this period about devices for atrial fibrillation.I think now once the dust has settled, most
electrophysiologist believe there's very little role of pacing for treatment of
atrial fibrillation.

Certainly
the magnitude of improvement we saw in this study has not been seen in any
pacemaker study that I've been aware of for atrial fibrillation.When I look at the population, look at the
current understanding of the data and then look at the procedure, except for
that initial anterior line that was dropped from the second phase of the
protocol, we're ablating the septum which is far away from the sinus node, the
flutter line which is way far away from the sinus node.Even though the posterolateral line is not
an anterior line along the crista where the sinus node would be but it's
posterolateral.So there is no lines in
the region of the sinus node.

I
would have a hard time understanding from a pathophysiologic basis.When we go to ablate the sinus node and some
of the inappropriate sinus tachycardia, it's virtually impossible even when we
deliberately try to do that.For many
reasons, I don't think the pacemakers are a complication of theprocedure.In most of the patients who had it, there's good documentation of sick
sinus syndrome prior to the procedure.

DR.
MAISEL:Okay.I saved what I consider the most important issue for my last
question which has to do with the assessment of the pre- and post-procedure
atrial fibrillation.I just wanted to
review what we stated as the primary effectiveness endpoint which was the
reduction in symptomatic episodes of atrial fibrillation assessed six months
post-procedure compared with the patient's baseline frequency.

For
subjects with greater than or equal to five episodes, they were required to
have a 50 percentreduction.For subject with three to four episodes,
they were required to have a 75 percent reduction.These reductions were to occur in patients taking the same or a
reduced dose of medication.

There
are several important potential sources of bias in the data collection that I
would like to highlight.One has
already been mentioned that patients were aware that a certain number of
episodes were required to be admitted to the study.I'm not that troubled by that.Patients didn't know exactly how many episodes they needed to get in the
study.If anything it would make them
more likely to make transmissions.We
may get a truer incidence of the pre-procedure atrial fibrillation.

To
me much more significant are the post-procedure monitoring issues.During the six month post-procedure,
patients were supposed to transmit recording when they were symptomatic and
transmit weekly recording whether or not they were symptomatic.That would be a minimum of four recordings
for all patients and close to two-thirds of patients did not follow the
protocol.They did not make the minimum
required number of transmissions.Just
over one-third made the required number of transmissions.

I
understand there were other ways of trying to follow them up with EKGs and
visits, etc.The lack of required
follow-up has very important implications for the interpretation of the
data.A patient who doesn't follow up
in my mind should not be classified as a success but should be classified as
missing.My question for the FDA is was
any data or analysis performed classifying those patients that didn't meet the
minimum of four transmissions classifying them as missing rather than as a
success?

DR.
EWING:This is Lesley Ewing.That's a very good point.No, we did not do that.If the patient at the six month
post-procedure said they didn't have any episodes but they could have had them
in the fifth month or the seventh month and they did not have transmissions, we
did give that to the sponsor.I think
that's a generous assessment.

DR.
MAISEL:I would agreed with you.Certainly there's recall by us and patients
who show up may not remember two weeks ago that they had a brief spell or what
have you.I'm very troubled by the
large number of patients who did not have adequate follow-up data.My final comment would be to note that
patients that have withdrawn from the study prior to the six month for things
like AV node ablation, I agree should be classified as failures and just not
evaluated for the effectiveness endpoint.These patients clearly likely had frequent atrial fibrillation and
should be failures.

So
even if you accept the transmission data as valid, then 42 of 88 patients or 48
percent reached the primary effectiveness endpoint and of those 24 of the 88 or
27 percent have what we initially in the protocol defined as clinical
success.So these are the main issues
that I had.Perhaps we can discuss them
further later.

CHAIRMAN
LASKEY:Great.Thank you, Bill. Why don't we go to Al Waldo
and have him render his comments.Dr.
Waldo.

DR.
WALDO:Thank you.

CHAIRMAN
LASKEY:Yes, sir.You have about 15 minutes.Okay?

DR.
WALDO:I don't think I need that
much.I do have some important comments
to follow-up on the remarks you've just heard.One of the things that concerns me is what appears to be the lack of
rigor in obtaining some of these data.I think for me the most worrisome thing is the lack of the transmission
of the transtelephonic monitoring.

The
crux of the study is the decrease of the burden of atrial fibrillation.As my old mentor used to say, "I would
love to believe you but you have to provide me with some evidence."The trouble is as we've just heard my
colleague say before there's precious evidence missing.You just can't assume that because they
didn't send anything in that nothing was going on.

I'm
also concerned especially with since so many patients had gotten pacemakers
symptoms may have disappeared from that.There are a bunch of people that got AV node ablations.There are a bunch of people who got more
amiodarone.If you start adding all
these little things together, they built the stone statue but on clay
feet.That's the problem.That's my biggest concern.

I'm
not sure if they would like to comment further on that I would like to hear
what they have to say.But I'm very
concerned that the critical data that we really need to believe them are not
there.That is not sufficient data
rigorously obtained to show that indeed with this technique.You heard both Dr. Kay and Dr. Calkins were
skeptical at the beginning of this study that this would work.Those of us who may still be skeptical about
it need to be shown.

I'm
quite willing to be a believer but they have to provide me with enough evidence
so I can believe them.I think the
missing evidence for the most part for me is the transtelephonic monitoring
transmissions.I saved the page.Data submitted on only 83 patients 22
patients with no transtelephonic monitors at all, 41 patients only had from one
to three.So therefore almost 64
percent were poor compliance with the transtelephonic monitors over six
months.This is to me is the Achilles
heel of what's been shown to us today.

DR.
CALKINS:It's Hugh Calkins.Just a few comments.The goal of treatment of atrial fibrillation
in the patients was improvement of symptoms as reported by patients.So I would agree that when there's no claims
that this procedure cures all atrial fibrillation and you can stop Cumidin,
this is to make patients feel better.

Again
it's very easy now five years later to look back at this as to how the study
was designed but the essence of the study was to say six months after the
procedure we wanted you to transmit every time you have symptoms.If they don't have any atrial fibrillation,
they don't have any symptoms.They
don't do any transmissions.

Then
all of a sudden, you say there's no transmission so you can't count the
data.But that is the data.So the question really comes down to when
the patient's feeling well, when they are doing just fine, going about their
life and going to work and whatever else, do they take the time to put this
thing on to transmit into the company and so forth?

Now
I think the strictest look at the data you'd say if there aren't four transmissions
or some months there might be five transmissions, then we should say that these
patients are non-compliant and ignore all the data even though the patient
showed up and sitting there in clinic looking you in the eye and say "I'm
feeling great and I've had no atrial fibrillation and I feel tremendously
improved.Thank you very much for doing
this procedure."And you ignore
that the patient that you had at the end of the day.

That's
what we are trying to accomplish.We're
trying to look at the patient when they come back to follow-up and say
"Are you better?Are you satisfied
with what I did for you?"They say
they are.And you say "Because you
didn't take the time out of every week five weeks in a month to transmit the
episode data, you might as well not have been in the study and let's exclude
any look at the data."

I
think one could argue that we want to at least prove that they have these
monitors and they know how to work them still and they are still alive. We know
they are alive.So let's look at a more
reasonable endpoint and say "Did the patient transmit at all that month
when they are feeling fine" and call that a compliant patient. To my
mind if you look realistically at patients, they're feeling fine at six months
and we're learning about this.This
will be important for future designs of studies about having things that
patients don't have to trigger themselves.

There
are some new technologies coming out now that can autorecord and that may be
what we need in the future but this technology was not available.To my mind that is a more reasonable way to
look at compliance meaning did they transmit once.

If
you look at the way you slice the numbers and the way the numbers would get cut
either look at the FDA's way of looking at it or our way of looking at it,
there are two places where we really lose patients.One is this flutter line.The FDA statistician brought up the issue about the picture and you have
part of the picture so how do you know what the picture shows.I think in this case you know what the
picture shows because it's a flutter line.So you have a duplicate of the missing corner of that picture.It's a flutter line which is interchangeable
regarding what catheter you do it with.The flutter issue at least from a clinical perspective to my mind is
inappropriate and it excludes those patients unless you look at the true
meaning of what we're trying to do here.

Then
with the event monitors, you may say "Only include patients that
transmitted once that are at least somewhat compliant."At least, they know how to use it and then
they'll transmit symptomatic episodes.So if you add those two things in, then you quickly go from a 44 percent
success rate which I think is still very good for a safety procedure in a
refractory.Then you add in the flutter
line patients and you end up with a success rate somewhere between 40 and 85
percent or 40 and 62 percent or whatever it is, somewhere around a 50 percent
number.

I
think your points are well taken and we're all learning about study design from
this study which I thought was very well designed at the time and very well
carried out.To say that it just has
clay feet I think ignores the fact that these patients showed up in clinic and
said how they felt and they felt better and said they had no atrial
fibrillation episodes or a marked reduction which at the end of the day is what
we are trying to achieve.

DR.
WALDO:I have to tell you.I respect you very much and I respect what
you are saying but in the end we have to try and be very objective.I think objectively the data just aren't
there.I hope you're right.I wish you're right but I don't know how we
know.

To
me, it's not just the TTMs.When you
add up the number of pacemakers, I think pacemakers alone make the symptoms
sometimes.Who know what the symptoms
were even if the patients had bardycardia before and that's why we were
symptomatic?There are so many
reasons.Then a bunch of patients got
AV node ablation beside.A bunch more
got increased amiodarone which I believe and I think we have to agree may play
a role in controlling rate.

So
when you add all the other little things to the fact that there's poor
compliance and objective evidence with TTMs and what's going on.I was probably the very first paper back in
the days when we did the TTMs and patients called in saying they had atrial
fibrillation and they didn't and patients called in saying they had sinus
rhythm and they didn't.We know about
all those things and those data are so well documented now.

It's
not just the TTMs.The spin you put on
it I understand and I'd love to believe you but I think in the end it's
soft.It's not hard data and I'm
worried that this is so critical to everything you're trying to say.On top of that, a bunch of patients had
increased amio or got amio for the first time.I know some patients went off it.That's good but a bunch of patients got more amio.A bunch of patients got pacemakers and a
bunch of patients got AV node ablations.All those are going to impact symptoms.

Controversial
or not, just the pacemaker alone some people still claim even a single site
patient if the rate's fast enough will impact the incidence of symptoms and
atrial fibrillation.So without trying
to be contentious in the least way, I'm just trying to be as objective as I can
as my old boss said "I'd love to believe you but I need the
evidence."That's where I am at
the moment.It's very troublesome to me
that the critical chunk here that I think is needed to hold your statue up is
too soft.

DR.
KAY:Al, let me just address a couple
of these things.The pacemaker issue
was something that I asked the company to show me as well.If the patient has AV node ablation, I think
we would all agree that those are failures of this procedure.I don't think we would argue with that.That's a failure.They would be willing to concede that too.

For
those patients who got a pacemaker after the six months when the efficacy was
obtained, I don't think that should count them as far as the efficacy.Those data came in before they got a
pacemaker.If you look at the patients
who actually got a pacemaker carefully looking at their baseline sinus rates
and I went through everyone one of them, I think there are two patients that I
would agree are a complication or that I would think ought to be classified as
a complication.The other ones really
weren't.Their heart rates weren't the
same.

Your
point about amiodarone I think, Al, that's not quite right.There were actually 18 patients on amio
before and there were 16 afterwards.Your point that a bunch of people were put on it isn'treally true.There were more people that came off it than were put on it.I don't think that really relates.

Then
the last issue which I think is a troublesome issue is the TTM compliance.Just asking ourselves, how would you do it
differently?I think it's the art of
possible.I don't know back when this
study was designed that there was any better way to do and I'm not sure there
really is any better way to do it today to find out.You have an independent person calling them, you have independent
people reviewing this and I think transtelephonic monitoring is about as good
as we have.

It's
really the art of the possible.The
company did what they were asked to do and they did it probably the best they
knew how to do it.I'm not sure any of
us could do any better.Even if you say
"We'll cut down and look at these numbers" one thing that's hard
evidence is that data you can look at anyway you want.That procedure is actually safe.

Efficacy
whether it's 60 percent or it's 40 percent for a right-sided procedure with
very low risk is actually probably clinically significant and it's something
that I think a lot of physicians would actually use because it's simple to do.Those are the ways I would respond to your
very legitimate comments.

DR.
WALDO:Again I remind unconvinced.I think that there are a little things.Maybe we can add up the numbers.Was it seven or eight patients being put on
amio and how many patients got pacemakers before the six months and so on?They just add up and it just makes data
soft.Let me ask you one last question
then.On the basis of this study, my
three EP colleagues who presented at this meeting for Cardima, are you planning
to do these kinds of lesions on a regular basis on your patients who are
symptomatic and who you can't cure otherwise?

DR.
KOCHERIL:Al, this is Abe
Kocheril.I will answer that
question.I just wanted to inject that
in our trying to figure out how to address the TTM issue one of the last things
we did was to look at a multi-variate analysis of what predicted
transmissions.This is also going to be
on the soft side but what was found was that it was people who were of
relatively younger age and people with fewer symptoms who were less likely to
transmit.That again won't satisfy the
legitimate questions you're asking.

The
other question is would we use this catheter and I probably have more
experience with this catheter than most people around.What I do in my practice is this is the
first ablation procedure that I offer to patients who have drug refractory
atrial fibrillation.If this low risk
procedure fails, we still have the option of going to the left side and doing a
pulmonary vein isolation.

Despite
the lack of rigorous data to satisfy your mind, patients do well and it's very
little of the time that I actually have to go to pulmonary vein isolation.When I do, I get about a 50 percent success
rate there.Yes, we will use the
catheter.One of the issues that we are
struggling with is how best to use it.This study as Dr. Calkins mentioned was developed awhile ago and things
would probably change if we were trying to study it now.

One
of the things that I'm looking at at our center is trying to map atrial
fibrillation from the standard point of Chaos theory and trying to analyze it
from an oscillator model and trying to determine where the ideal lesion
location should be rather than just saying we're going to put in three lesions
and compartmentalize the right atrium.I don't have any data to present on that.I just highlight that I think it's safe and effective the way it
is now but as more clinicians have a chance to useit, we'll get a better handle on how best to use it to benefit
the population of patients with atrial fibrillation.

DR.
CALKINS:Al, I just have a couple of
comments about where it would fit into the armamentaria of the
electrophysiologist.I think it would
have a very important role.Right now,
in the absence of this catheter being available, people say that their one
option is a pulmonary vein isolation.Anyone who is doing this procedure realizes there is a learning curve
and the learning curve is very rocky as you go up on it and the complications
are like no other procedure that's ever been done in an EP lab.

So
right now we have the electrophysiology community in a tough spot.They're hearing about pulmonary vein
isolation.These articles are showing
in circulation every week.They are
getting pressure to do something for atrial fibrillation.All of a sudden they start doing it and the
complications occur.

We
don't know where this procedure is going.It's evolving rapidly from periostial ablation to perianatomic ablation
to different mapping techniques to different energy sources.That's very much of a moving target.

What's
nice about this procedure is that it's not a moving target.Here's three lesions which can be understood
or reproducible.It's clear how to
deliver them.It's a first step.So where it fits in for a center like mine
where we can do whatever we please, we'll tell the patients that they have an
option.If they want to go for the home
run, the cure, and they're willing to accept a procedure with higher risks
that's in evolution and so forth, we're happy to go ahead and do a pulmonary
vein isolation.

If,
on the other hand, that scares them, the idea of doing a procedure where
pulmonary stenosis (PH) or stroke ?- are clear
risks but they say "I want to do something.I'm refractory to drugs".We'll say "Let's go head and do a right-sided procedure, get that
done and see if you improve.The data
suggests that there's a very good chance that will make you better.Then if you don't improve we can always
three, four, five, six months or a year from now do a pulmonary vein isolation
and hopefully by then we'll know what tools are the best to do it with and
we'll have a little more information so we can do it more safely."

For
the other hospitals that don't have the ability to do pulmonary vein isolations
safety or effectively, this is a procedure that instead of just doing a flutter
line which I think does very little in this setting they can go in, do an
atrial fibrillation ablation procedure, give the patient some benefit, make
them feel better and then in the future, you'll have to a pulmonary vein
isolation as an adjunctive procedure. That's a better way to be
approaching atrial fibrillation rather than just doing a high risk procedure
right from the outset.

DR.
WALDO:I really have no other
questions.I have one last comment
though.I was surprised in the material
that we got from the FDA that the company provided.I was surprised that in 2003 that the company still stated atrial
fibrillation was due to multiple ?- I think
that was the premise for a lot of this which I still find as a principle that
the technology is way ahead of the science.That's always a problem.I think
that's where we are now and we have made advances in this field.That'sfor sure.Thank you very much.

DR.
EWING:I'd like to present the panel
with some additional information if I may. This is Lesley Ewing.Just to give some information that the
Agency has about transtelephonic monitoring, there isanother submission that's under review.The data eventually will be available but they're in a follow-up
of another ablation study.They are
able to get near 90 percent compliance with transtelephonic monitoring in
asymptomatic patients.So the Agency
knows that it is achievable.Thank you.

CHAIRMAN
LASKEY:Okay.David.

DR.
SCHWARTZMAN:I think I have more
comments than questions.First of all,
I would like to echo the others on the panel in stating appreciation to both
the sponsor and the FDA for excellent presentation and clarification.At the end of the day, the numbers can only
take you so far and then there's interpretation.I respect the bias to either side.

I'm
going to bring to bare the reason I'm here which is based on experience,
primarily personal experience not with this particular technology but with the
electrophysiologic, anatomic and clinical target and the vagaries and
difficulties therein and also considering the data as presented.I first want to make comments against this
proposal and then I'll make comments in its favor.

First
of all, against, the starting point to me is that this claim of continuous
linear lesions is certainly unproven.Again not having primary experience with this and without data presented
otherwise based on my own experience, I think it is likely that the vast
minority of these lesions were continuous in the sense of transmural and
contiguous, therefore acting as arcs of conduction block as conceptualized.

Secondly,
I think the electrophysiologicefficacy
that is EKG burden reduction is really not clear to me but my guess is it's
probably under 50 percent at six months.Again bringing experience to bare, longer follow-up is going to probably
likely beworse.I know what the reducing burden data had
shown from three to six months but again primarily from my own experience this
is not a disease that remodels favorably over the long haul.

In
that regard, I'm concerned that we're approving a protocol or a technology
technique that is going to end up being a waste of patient/physician time and
money.My own personal experience with
right atrial linear ablation although with similar numbers early at two years
only 10 percent of these patients remained without another procedure whether
that be pharmacologic or non-pharmacologic.So at the end of the day long term benefit is hard to find.

Finally
I have concern regarding the safety of this technology in its inevitable use in
the left atrium as soon as it gets into the hands of those of us who have our
own visions about this technology.Some
of the charring issues, the entity of thermometry which I think is a terrible
method of guiding power titration and generally under represents interfacial
temperature which is what relates to charring and presumably cardioembolic
material.We get away with a tremendous
amount in the heart particularly in the right side.I'm concerned about its extended use whether or not it's labeled.

On
the favor side, it is clear that some ablation burden is accomplished
here.It is unclear clinically that
this concept of continuous linear lesions are either needed or important.So in that regard the technology because it
achieves some degree of ablation burden is a viable ablation technology.

A
substantial minority of patients appear to experience a significant burden
reduction.That is electrocardiographic
burden.A majority of the patients
appear to feel better.So clinical
burden reduction is apparent and notwithstanding the limitations that have been
laid out pretty clearly.But again
practically it is very difficult these kinds of studies without a control arm.

As
already stated in the absence of longer term data notwithstanding our arrogance
about pulmonary veins and left atrial ablation and left atrial being the seed
of all evil, it is probably reasonable to start with the right atrium.This is particularly true and a very
important point for the masses of electrophysiologists who are new to this area
who are getting tremendous pressure from their community to do something as
these guys said.It is a time extending
situation that allows that experience to be gained and refinement of left
atrial ablation technologies that will have also served a viable purpose.Those are my comments.

CHAIRMAN
LASKEY:Wonderful.Thank you.Sharon.

DR.
NORMAND:I also echo the comments and
enjoyed the presentations by both the sponsor and the FDA.I actually have several comments and not
surprisingly they have to do with analysis.I have some questions about really which patients should be included in
the analyses.I do have questions about
sample size.

I
have some very important questions I feel about determination of the primary
endpoint.I have some comments about
the secondary endpoint as well.I know
not much has been said about that but I do some comments about it.I do have some questions regarding some of
the assumptions and verifications of the assumptions that have been made both
by the sponsor and as well by the FDA.

Part
of my question at the very beginning about clarification of the numbers related
to really what are we studying here.What's the investigational device?When I look at the numbers that I ask for clarification for, it seems to
me that some patients shouldn't be included.

This
is not a clinical trial. This is an observational study.There is no sense of intention to treat in
this type of analysis.So I'm a little
confused I guess as to why some patients would be included in the
analysis.I'm stating that.I don't think anybody can argue me over to
the other side on that.I just want to
lay that out.

That
is some patients and I think it's at least 20 if I understand the numbers
correctly that I think I would not have included certainly in the primary
endpoint.They didn't receive the
procedure, the device for which we are supposed to be assessing.

I
do have questions that hopefully someone can answer regarding sample size.This has a little bit to do with maybe the
bouncing of numbers that I've seen both from the FDA as well as from the
sponsors in terms of the number of available observations at baseline and at
six months.

I
just want to get a sense of why some of those numbers were going away.I understand that some people are lost to
follow-up.I'm just trying to figure
out what the right denominator here for the primary endpoint.Is it 81?Is it 87?Is there any meeting
or convergence of the minds in terms of that number?

The
reason why I'm raising this issue is for some reason there was longitudinal
data collected yet no use of it certainly in terms of analysis of the primary
endpoint, some use of it for other answers.I'm a little concerned about that.I just want to get a sense of why we're missing some data for the
primary endpoint.I know maybe the
sponsor can tell me.Is it 87?Is it 83?Is it 81 and whether or not the 20 or 22 depending on how you count
people are included in that denominator?

Let
me be specific.You have a number for
your primary endpoint.Either it's 87,
83 or 81.It's in the 80s.Are the 22 people who didn't report included
in that number that is who report about their symptoms included in that
denominator?It should be simple.It's yes or no.

DR.
KOCHERIL:Abe Kocheril.A very good question.Of the 22, we had redundant measures as
we've seen.Based on symptom reduction
by other measures, the office visit, case report forms and by the AFSS, 10 of
the 22 did have the requisite symptomatic reduction.They were in the analysis as successes.The other 12 did not.

DR.
NORMAND:But are they in the
denominator.I don't care about the
numerator.They are in the denominator.

DR.
KOCHERIL:Yes.

DR.
NORMAND:Terrific, okay.So I'm going to ask some more questions
about the primary endpoint.I'm just
curious as to why quasi experimental design wasn't used.In other words, you have an observational
arm.You're looking at prospective data
collection.You could have had some
sort of other group.Certainly the
other that I'm throwing out here could have been used.Why did you just go for a interruption time
series we would call it in terms of not having a control group?

DR.
KOCHERIL:I don't understand the
question.Please phrase it again.

DR.
NORMAND:Why is there no prospectively
a control group?

DR.
KOCHERIL:There's a history as to how
this protocol was developed.It was a
collaborative effort between Cardima and the folks at the Mass. General and the
FDA.For people who are drug
refractory, this was the recommended setting design.If they weren't drug refractory, then a randomized control arm
would have been used.

DR.
NORMAND:Okay.I noticed that you have a multi-center
study.Did you adjust for the fact that
you have multiple sites in the analysis?Just so you know, all my questions are just going to add more variability
to your answers.I just need to know
whether or not that was adjusted.

DR.
KOCHERIL:It was not weighted if that's
what you mean.Basically all the
patients were thrown in --

DR.
NORMAND:No, it's not a weighted
question.It's whether or not there was
an extra component of variation due to the fact that you had multiple sites.So probably not.

DR.
KOCHERIL:I'm not aware if we did.

DR.
CALKINS:Hugh Calkins.I'm not a statistician and it is true that
many sites participated in the study.I
think actually that's a strength of this study.

DR.
NORMAND:I'm not arguing that it's not
a strength.

DR.
CALKINS:Single center studies where
Center X can 100 percent success during atrial fibrillation with a pulmonary
vein approach.In that person in that
center with whatever they used for follow-up, they can get those results.In this study, you had 20 different centers
and each center may have more than one investigator doing the procedure and the
data was pooled.There was not a subanalysis
but I think that speaks to the value of widespread of hands that these are the
results that you will get with this technology.

DR.
NORMAND:I understand.I do think it's a strength but statistically
you also need to adjust for the fact that you have multiple centers.So didn't adjust?

DR.
CALKINS:No.

DR.
NORMAND:I guess the next thing is
whether or not you did a stratified analysis.I noticed in your sample size calculations it looked like you just did a
single analysis but it looked like it really should have been a stratified
analysis depending on the baseline entry.In other words if I understood correctly and I may not have understood
correctly depending on the number of episodes at baseline, it was a different
expectation in terms of the size of the benefit that would have counted as a
success.Is that true?

DR.
CALKINS:Yes, if they had more frequent
episodes of atrial fibrillation, they only had a 50 percent reduction.

DR.
NORMAND:Got you.

DR.
CALKINS:But what we saw in the data
and if you remember the slide showing the 81 patients, the most symptomatic
patients didn't have a 50 percent reduction.Those were the patients with the 90 percent reduction in atrial
fibrillation episodes.So although that
was the cut-off in fact it was a non-issue because the most symptomatic
patients had a 75 percent reduction just like the less symptomatic.

DR.
NORMAND:But it wasn't a stratified
analysis.

DR.
CALKINS:No.

DR.
NORMAND:I just want to get a little
better understanding of the definition of the primary endpoint.Let me just be specific so you understand
exactly what I'm asking.I don't want
to waste time.My understanding is that
the number of symptoms, let'ssay in
the baseline period and then the sixth month period, the patient was supposed
to report weekly.Is the total number
of symptoms that's represented in the baseline period over the four week
reporting period or is it an average per week?

DR.
CALKINS:No, it's a total number.They were instructed to transmit when they
had symptoms of atrial fibrillation at baseline and then during the sixth month
point.So the routine weekly
transmissions when they were asymptomatic do not affect that number.The number is how many symptomatic episodes
of atrial fibrillation.What we found
is baseline when the patients thought they were in atrial fibrillation only 50
percent of those transmissions actually showed atrial fibrillation --

DR.
NORMAND:I'm sorry to interrupt but I
think you misunderstood my question. I
probably wasn't clear in the question.My question is the reporting is supposed to be on a weekly basis.Sometimes some people reported four weeks in
baseline period and maybe some people just transmitted for two weeks.Is that correct?

DR.
CALKINS:No, the patients were
instructed to transmit for a month.Every time they had symptomatic atrial fibrillation, they would transmit
anytime throughout that month whether it's once a day, whenever they had
symptomatic atrial fibrillation they were supposed to transmit.Even if they were asymptomatic, they were
supposed to in addition transmit once a week regardless of symptoms.

DR.
NORMAND:I got you.

DR.
CALKINS:The number we're looking at is
how many times they had symptomatic atrial fibrillation that was transmitted
and confirmed to be atrial fibrillation baseline versus at six months.

DR.
NORMAND:See my concern is coming in if
there's a different exposure period for the reporting ?-

DR.
CALKINS:The same 30 days.

DR.
NORMAND:But if some people even though
they were supposed to report all the time don't then you are measuring on a
different period of exposure period if that's what you want to think of it.

DR.
CALKINS:Yes, I think in the absence of
an auto-triggering device you implant in the patient that takes them out of the
picture all you can do is hope that they are as compliant as they can be.There's no way to continuously monitor them
with today's technology.

DR.
NORMAND:Then that led me to the
question of whether or not it was adjusted in the analysis in terms of let's
say at month six when they are reporting when they are supposed to be
transmitting weekly.If you had that I
transmitted three times in month six and you transmitted once in month six and
let's say for me there were two episodes, did you account for the fact that I
transmitted three times and you transmitted once the information?

DR.
CALKINS:No, because the patients were
supposed to instruct when they had symptomatic atrial fibrillation so they may
just transmit 20 symptomatic atrial fibrillation episodes that occurred in a
week but not transmit the asymptomatic times.So there was no real way to look at that or correct for that or divide
that.Although half the patients had no
atrial fibrillation episodes at all.So
depending on how you correct for zero, it's still zero.

DR.
NORMAND:I'm going to act on the
concern that other people raised about the 20 or 22 people who didn't
report.One can't assume that it's
zero.I guess I'll argue the other way
even if I went to see my doctor, I might be afraid to say that I did have a
problem but forgot to transmit.I think
there are some issue with actually assuming it's zero.

I
understand that there was some verbal communication which I take exception to
in terms of the reliability of that.I
understand you did the best you could.But that also means that you have differential ascertainment bias in
mixing the information from those that actually transmitted and those that
reported verbally.I'm just wondering
about the bias that it might introduce.You probably don't have an answer to that but it does just add another
level of concern about the quality of the data for the primary endpoint.

I
think a prudent approach should say it's missing.Then the missing data one needs to think about other assumptions
about the missing data.That is whether
or not you assume things were missing completely or random.Missing at random I realize these are
technical terms but I'm sure somebody does your statistics.There is some things that you worry about in
terms of those types of assumptions.

I'll
go on to the secondary endpoint.I'll
be brief about that one.This is just
my being naive.I'm not sure what a
clinically important change in that particular SF-36 scale is.Is 10 point clinically meaningful?I have no idea.

DR.
CALKINS:I think that is felt to be
that clinically meaningful.

DR.
NORMAND:Okay.I think in the reading of materials I
understood that you did something with that other scale which I'm going to
forget, that AFSS scale.I didn't
understand what was written.It sounded
like to changed the scoring of that second scale.Is that correct?In other
words, how you actually score a patient on the second scale.

DR.
CALKINS:If you look at the two scales,
the atrial fibrillation severity scale is particularly designed for patients
with atrial fibrillation.So if you
look at the results, that's where you see consistent improvement and greater
than an average of 10 point improvement all across the board.For the SF-36, there were just two or three
of the seven markers that showed that 10 point improvement.Those were the ones that were most
significantly depressed but that's a very non-specific marker that doesn't
specifically look at atrial fibrillation.Let me have our statistician speak to it.

MR.
STUBBS:Hello, I'm Harrison
Stubbs.I'm a paid consultant for
Cardima.I have no equity in the
company.I'd like to comment on a
couple of things, just to step back a few steps if possible.

First
you asked about a stratified analysis of the success episode reduction
according to baseline categories.We
did that in response to an FDA deficiency and we turned that into them.Frankly we saw no trend or real difference
in the response rate according to baseline number of episodes.

Secondly
regarding the AFSS instrument, that is not scored on 100 point scale.We wanted to convert that to a scale that
would be congruent to the SF-36 domains.Consequently we scaled it to an 100 point scale with low numbers being
bad and high numbers being good.

We
were concerned about compliance too.In
response to FDA's concerns, we took a good look at compliance.We categorized compliance a couple of
different ways.We looked at those that
didn't transmit versus those that did.We looked at those that transmitted three or more episodes in the month
six versus those that transmitted fewer than three.We chose that break point because it divided the sample in about
half so we figured we optimized the discal power to address any differences.

We
looked at AFSS instrument in particular because the three scales of that
instrument are episode frequency, severity and duration.Those three go in to make up the total AFSS
score.In looking at that and also the
SF-36 according to these two ways of categorizing compliance at six months, we
did not see any significant differences in any of those parameters.

It
is important in particular that the AFSS scales showed no differences because
the concern one always has with non-respondents and non-compliers is that they
are doing characterizing worse.At
least according to the AFSS score which is an AF specific quality of life
instrument there is no evidence of that in the results that we looked at.

DR.
NORMAND:Thank you.I think one of the concerns I would have
with the analysis of the secondary endpoint is power for you not to find
differences.I think you have some
small sample sizes to make comparisons.Moreover you have several subscales that you are comparing.If anyone cares about multiple comparisons,
I don't think you adjusted for the multiple comparisons you were doing.

MR.
STUBBS:No, but nevertheless there were
none that were statistically significant.

DR.
NORMAND:I'm just saying that it's
power.A lack of power would say you
might not find differences.

MR.
STUBBS:That's true but you have to
balance that against the multiplicity of the number of comparisons.

DR.
NORMAND:I actually think that's all I
have for now.Thank you very much.

CHAIRMAN
LASKEY:Chris.

DR.
WHITE:Thank you, Warren.I actually don't have much really to add to
what's been said by my colleagues.I
would like to ask the PI though maybe in the sponsor that as many of us are
involved as being investigators in trials, I don't quite understand the freedom
of your investigators to deviate from the protocol.For example, the 20 times that study catheter was never used.

Hugh
was mentioning up here that if they were familiar with the catheter, they might
abandon a little easier and gone with another catheter.I don't understand never trying the
experimental catheter.What was going
on in their minds?These would be
protocol deviations that would come up as red flags right off the bat.I don't know why the waters were allowed to
get so muddy down the road.

DR.
KOCHERIL:Abe Kocheril.I'll try to tackle that one.In Phase IIb before the NavAblatorTM
was available, the investigators were told to use the REVELATION_ Tx and it was
tried.Hugh pointed out the variables
that are specific to the operator and basically several of the investigators
right away had bad experiences trying to get an adequate lesion and the
investigators started deviating in Phase Iib.

In
Phase III, the NavAblatorTM was offered as an option but by that
point there was already this mindset that a flutter line is a flutter line and
that what you used for it didn't make a difference.This deviation was tolerated because on the part of the
investigators we felt that way too that no matter what you use to get a flutter
line, it doesn't matter.You just need
to get a flutter line as part of this procedure.

DR.
WHITE:Was there insight at the
timethat you would have that price to
pay today?

DR.
KOCHERIL:No, I think we can.

DR.
WHITE:Was there insight that you were
contaminating your data that you weren't following your own protocol that you
set?

DR.
KOCHERIL:Looking back on it, that's
certainly an issue.At that point, this
was the subject of investigator meetings and we would get together as a group
from all the 20 sites.In all the
discussions of the flutter line, the prevalence of opinion was that a flutter
line is a flutter line.There wasn't a
distinction made.

I
also add that the getting a flutter line with Tx is also a matter of
persistence and dedication to it.Having had the earlier experience with the earlier version of the
REVELATION_, I did persist longer.What
it takes to get an adequate flutter lesion if you are going to use that
catheter to do it is basically making multiple loops and getting into the nooks
and crannies of the flutter isthmus to be able to do it.That's time consuming.You have to be persistent to do it.It can be done.For most investigators since the flutter line did not seem to be
what would make or break this protocol, it was easy to slip over to a catheter
that they were comfortable with.

DR.
WHITE:Were any of your sites
terminated for non-compliance with the protocol?

DR.
KOCHERIL:No, I don't think they were.

DR.
CALKINS:Just one other comment, it is
true that with the flutter line we had these 28 patients that were ablated only
with some alternative catheter and the NavAblatorTM or linear
catheter was not used for the flutter isthmus right from the get go.This really reflected the bias of the
investigators to do what was best for the patient.They felt the other catheter got the job done better.

DR.
WHITE:That may be so but you're asking
us to approve this data upon protocol you wrote and then you deviate from that
protocol.I don't know how to make up
for that.I understand what you just
said.When I enroll patients in
protocols, I do things according to protocol.I don't get a choice to say what I think is best for the patient.

DR.
CALKINS:Two points.The linear lesions which is a really unique
feature of this protocol were all done with the REVELATION_ Tx catheter.I think that's what we're mainly focused on
today.The issue about the NavAblatorTM
and theNavAblatorTM ended
up being only used in 60 patients and whether that should be officially part of
the system where we now have an improved flutter catheter on the market that
should be available to create a flutter line with whatever catheters you
want.That makes sense.

In
the beginning of the protocol the way it was initially designed was it
instructed the investigators to first try the flutter line with this linear
catheter but it did not say you cannot use any other catheter to get the job
done.It said first try this.Then use what you otherwise would do as far
as clinical practice.

So
the investigators that started going to use another catheter, it wasn't that
they were deviating from the protocol. The protocol said first try theirs
but to get the flutter line, you can use whatever you want that's available to
you to get the flutter line as part of the protocol. So it was not viewed
from the company's perspective as pull the plug in the center because that's
built into the protocol that the flutter line can be done with some other
catheter as part of the protocol.

What
we learned as this study started five years ago, there were 10 different
companies out there with linear catheters trying to ablate the isthmus.Guess what?It doesn't work with any of them.So we were trying to do the impossible.Then it just became this preference of catheter feel issue.But the protocol was not designed if the
flutter line was done with another catheter that's a failure.It was first try with our catheter, get a
flutter block with your standard clinical care.

DR.
WHITE:But you just said "Try with
our catheter and then if you don't..."You have a whole bunch of patients in here who weren't tried with your
catheter.

DR.
CALKINS:I know.By the end of the protocol, some of the
investigators really preferred X catheter and these were all these 4mm
catheters.

DR.
WHITE:But I don't understand
that.I'm in protocols right now where
it's clumsy to do the thing the study way.It takes a long time.I think if
you sign up for a protocol, you play by the rules.If you don't play by the rules, you get terminated.You get kicked out of the protocol if you
don't follow the rules.Or you pay the
price you're paying today for the confusion this generated.I think that's the lesson.

DR.
CALKINS:Yes, at least as investigator
for me there is no confusion.It's very
clear that a flutter line is a flutter line from a physiologic standpoint, from
a therapeutic standpoint.That's not
what we're here today is to approve a flutter catheter if you will or to look
at the safety or efficacy of a flutter catheter.We're really focusing on a linear ablation system.

DR.
WHITE:Actually you don't get to
focus.I'm focusing.

DR.
CALKINS:You're focusing.

DR.
WHITE:Thanks.What my problem is if you're sloppy enough
to do the protocol this way then I think that runs through the whole
study.That contaminates the
study.It's not that a flutter line
isn't a flutter line.It's that you
wrote the protocol and then you didn't stick to it.I don't like that.That
bothers me in terms of the reproducibility.

Al
talked a little bit about the rigor.I
think this is part of the rigor of following the protocol.I think it's the sponsor's job and the PI's
job to make sure people are sticking to the protocol.If they are not, then there is disciplinary measures and you
exclude them or you terminate them or you say "You're not playing by the
rules so you can't do this anymore."

I
just think you didn't do that.You
didn't take that very seriously. I'm
telling you from my perspective that it's a very important part of doing these
kind of investigations.You have to
have the discipline to follow through with what you and the FDA set about as
being your protocol.I just see those
deviations as problems.That's all I
have.

CHAIRMAN
LASKEY:I'm confused now.Are you backing away from the NavAblatorTM
portion of this PMA?

DR.
CALKINS:If the question is what is the
tool that I and the EP community would like to have access to, it's a safe
linear catheter ablation system.It's
not the NavAblatorTM.It's
the linear ablation, the REVELATION_ Tx.Quite frankly, we have plenty of catheters we can make flutter lines
with either on-label or off-label now that there are some officially
approved.I feel strongly there are all
completely interchangeable.

And
this catheter was never, the NavAblatorTM design, to be the best
feeling, best handling, best driving flutter catheter on the market.That was not the purpose.That was made to address the FDA's concern
about this issue Dr. White brought up about having a tool so that you can
complete it as best you can.

If
there is a tool that we need, it's quite frankly not the NavAblatorTM.Yes, we would like to have the whole system
approved but the critical thing is the REVELATION_ Tx which is the unique
technology that I think is most critical to making these other thin linear
lines that are essence of the procedure.

CHAIRMAN
LASKEY:All right.Is the only reason we're spinning our wheels
here about this because your sample here is enriched or contaminated by the
AF?How often do you encounter this in
general practice?Is this an unusual
group?You had a quarter of your people
with flutter.Is that usually an issue
with your garden variety AFs?

DR.
CALKINS:The issue here is part of the
protocol.The three lines that were
prescribed were the flutter line, the SVC line and the septal line.They are the three lines of this right
atrial linear approach that we're discussing.Much of the discussion of both Dr. Ewing and our discussion today is on
what catheters pulled out to make that flutter line.Now as far as patients in the study, they got in because of
atrial fibrillation.

CHAIRMAN
LASKEY:Right, but they have a large
presence of atrial flutter here.

DR.
CALKINS:Yes, and in any population
you'll see both atrial fibrillation and atrial flutter.If you show an EKG and they show rapid
flutter one time, atrial fibrillation the other time, I think the two disorders
go hand in hand to a large degree.

CHAIRMAN
LASKEY:For that matter, what goes on
in the RA may or may not go along with what goes on in the LA.Can the left atrium be fluttering and the
right atrium be fibrillating or visa versa?How does that effect this approach?

DR.
CALKINS:Dr. Waldo may correct me but
either the heart is fibrillating or it's fluttering.Yes, there have been some cases where you do some ablation
procedures and electro-isolate one part of the atrium which you can
refibrillate and the rest can be fluttering.In general at a given moment, you're in atrial flutter which is a
regular rhythm or you're in atrial fibrillation which is more rapid irregular
rhythm.

CHAIRMAN
LASKEY:We just need to be clear about
what it is we're treating here or what you're treating.I just had one comment statistical in
passing.When I was bored on a plane
ride, I went over your sample size calculation and I went throughthe upper and lower confidence limits that
you had quoted on page 14 for a 50 percent success rate.

Actually the calculations that I come out
with using the standard roughly 1.96 times your standard error giving you the
upper and lower limits, you don't make it at the .05 level. Did you go
through the exercise of your beating your lower 95 percent confidence limit for
your clinical success rate?If so, can
you point out where I erred?

MR.
STUBBS:Harrison Stubbs again.When we put the confidence interval figures
in the original protocol, that was done with the exact method as opposed to an
approximate method which you are using.But I'm unclear on your question regarding whether or not the lower
confidence limit was met.

CHAIRMAN
LASKEY:Generally you want to beat that
since you don't have a control arm here.You just have a single arm study. So basically you want to beat
some estimate of your estimated success rate.Generally you pick your lower confidence level and try and beat that.

MR.
STUBBS:Okay.

CHAIRMAN
LASKEY:Using the numbers that you
actually observed and computing the lower, it doesn't work.

MR.
STUBBS:Yes, I follow you.In the protocol, we chose the sample size of
80 as providing clinically acceptable precision for a wide range of possible
success rates going from 30 to 70 I believe.It turns out that a success rate of 50 percent gives you the worse
possible case.

We
did not set in any OPC or any particular minimum confidence level that we
needed to achieve because in discussions with the FDA statisticians it was
decided that it's not clear what level of success for this procedure would be
clinically useful.We were going to
leave that to the panel to decide.So
our responsibility in designing the study with 80 patients was solely to achieve
an acceptable level of precision.The
success rate fell where it may.It's up
to the EP community and the clinical community to decide whether that's
acceptable. Does that explain your question?

DR.
TRACY:I'm a bit more confused than I
was earlier this morning I'm afraid.One of the questions that I think is pretty relevant for thinking about
this whole thing is what is an acceptable level of effectiveness.We have a range between 47 percent and 81
percent.For a condition that in terms
of treatment, palliation is probably an acceptable outcome.Is 47 percent an acceptable level
effectiveness?I would argue that it
probably is.

Often
the thing that you do one day is not going to be the last thing that you're
going to do with that patient for the rest of their lives.So even though you may end up a year later
needing to do a pulmonary vein ablation, that probably is okay to give them a
year with some improvement in their symptoms.So even if you accept the lowest level of effectiveness, it's not
terrible.

I
guess though I'm troubled by the mixture of catheters that were used.I agree with you that a flutter line is a
flutter line regardless what catheter it's made by.I was playing with this across my knuckles and there's no way
this thing could ever make a lesion that would be effective for flutter.

I'm
a little troubled that a flutter line was made at all.I guess it comes to the question of what is
atrial fibrillation in the first place.How does it start and why does it perpetuate and what good is a flutter
line in fibrillation?That's a very
confusing piece of this whole puzzle.

The
other thing that I'm not so troubled by is the number of pacemakers having
taken care of a number of post-Maze patients and having put in Dr. Cox's
patient's pacemaker in about probably 10 to 17 percent of them after they've
had successful Maze.They always
presume to be on the basis of preceding undetected or poorly recognized sinus
node dysfunction.That's not such a
terrible thought to me that a fairly high percent would end up with pacemakers
although certainly those that had subsequent AV node ablations and pacemaker
implantation are failure.I think
that's pretty clear.

Another
piece of how the study was run is it's clear that people were trying to achieve
bidirectional block with their flutter ablations and they knew that they
weren't successful somehow.Either they
had ESIs in or they had Cardos in or they were doing pacing techniques to
determine bidirectional block.It's not
so clear to me that the other linear lesions were that systematically looked at
to know whether there was bidirectional block around the linear lesions.So maybe somebody when I stop talking can
comment on that.

DR.
CALKINS:Hugh Calkins.Cindy, the only line that was confirmed was
the flutter line in a conventional fashion with a halo catheter.The other lines the protocol said nothing
about confirming block or demonstrating block.It was you put the line in these positions.You demonstrate lesion creation by seeing some change in the
electrical properties of the myocardium.You usually see a decrease in electrogram amplitude in a very striking
fashion.

But
that was it.There were requirement for
testing verification and finding out if there's lines as David pointed
out.I would agree that it's very
unlikely that every one of these lines is continuous, transmural and anchored
at both ends.The chance of that is
very unlikely.

The
goal was lay these lesions down.Not
all of them are continuous, transmural and anchored at both ends.But does that strategy decrease atrial
fibrillation burden?This is really the
question that we're asking.David's
point is correct.We really don't
know.Does it have to be completely
transmural? What if it's transmural in part but not all?Does that have an effect?

We
were really looking at the strategy not with concomitant mapping systems which
makes the procedure go from one that's straight forward to one that's very
complex.It has to be performed in labs
and have all this fancy technology and adds tremendously to the overall
personal time, lab and equipment expense of doing that.

DR.
TRACY:Just to get a sense again for
the procedure, there are eight areas where energy is delivered a minute each so
that's eight minute per line.But some
of the procedure times were much longer than the 32 minutes.So how many lines per patient was average?

DR.
CALKINS:The way the catheter is
delivered is it goes through the NaviportTM catheter to be
delivered.Then you lay the catheter
against the wall.In some patients and
in some lines, you can have the whole catheter lines against the wall and be
able to burn sequentially eight electrodes and that would go fairly
quickly.If it's a lateral wall, you
would have to do pacing to make sure you don't have phrenic nerve simulations
so that would add some time.

But
more typically you wouldn't have perfect contact in all eight electrodes.Maybe only the first six or the first four
would have good contact.You do that
burn and then you just pull the catheter down to where the bottom ones started
and then put another four to six to eight burns in and then pull down until
you're down in the IVC.

So
let's say if there's three lines, each line took at least two catheter
positions to create it.Then you have
placement of standard catheters, creation of the flutter line, validation of
the flutter line and now we know that flutter lines are best created with other
types of catheters, irrigated tip or 8mm tip or high energies because it's
thick.That is one way that makes the
procedure shorter today when we are doing flutter ablation just because quickly
go to higher power technologies for that part of the procedure.

DR.
TRACY:Just a couple other things.A safety issue is that I noticed that there
were a relatively high number of skin burns.My guess is that those aren't as patiallated (PH).Those are related to radiation burns.I noticed some where were the skin patches
were, the R2 patches were but those act as antenna basically for the
radiation.The fluorotime was at least
in one of these cases 247 minutes which I would think that anybody would agree
that's excessively long.How hard is
this procedure?Are people going to
inducing radiation damage in patients by doing this procedure?

DR.
CALKINS:I think your question is a
good one in terms of radiation exposure.At least my interpretation data there was no ulcer formation.There was no clear demonstration of
radiation skin injury.I'm unaware of
any data saying that the defibrillator tab patches attract radiation skin
injury.

It's
clear that it's greatest near the tube right where the tube is located.If you have biplane or what system, that's
where you're going to get the highest skin exposure with some evidence of skin
injury usually occurring a week or two later.

Overt
evidence of radiation injury is clearly when you get these nonhealing ulcers
that are a complete disaster.There
were none of those in this protocol.It
is true.You should have a radiation
limit.In the old days in some of the
earlier studies, 40 minutes was an average fluorotime. In the study, we
looked at the cardiorhythm study where we looked at radiation exposure
times.Some got up to as high as 300 or
400 minutes.I think 450 minutes was
the longest for a standard SVT ablation.

It's
clear that there's a cutoff that we proposed in that paper.I think, realistically when you do that
procedure without using other technologies to try to validate lines when you go
straight for the flutter line to a flutter catheter that's designed for that
either an 8mm irrigated tip or whatever, the procedure takes one to two hours
with 40 minutes of fluorotime.

Any
electrophysiologist should know that there's a point where you should stop any
ablation procedure whether it's four or six hours.That's a message that goes with saying for any of these
procedures.I think your point's well
taken.Let me turn it over to Abe.

DR.
KOCHERIL:Abe Kocheril.On the burns that was analyzed further and
those were actually related to cardioversions and probably not related to the
radiation exposure.On the actual time
of the procedure, I mentioned earlier in my presentation that there is a
learning curve to it.When an
investigator is starting out with this procedure, they want to convince
themselves that they are getting an adequate linear lesion.They will take longer.

In
my center, we've gotten it down to under three hours for total procedure time
and 30 minutes or less for fluorotime.So if you take awaymeasurements, it could possibly be even quicker than that to deliver
these three lesions.

DR.
TRACY:Okay and then just a couple of
final points on the transmissions.There was a period of time at the beginning when patients were coming to
enroll in the protocol.AF was between
a month or if they didn't make it in a month they could be rescreened and they
might go as long as three months making symptomatic transmissions.As we all who take of atrial fibrillation
patients realize that not all of our patients are 100 percent accurate at
determining it.But the ability of the
patients to determine whether they were in atrial fibrillation or not seemed to
decrease after the ablation procedure.Is that some nerve damage that was done that reduced their ability to
detect atrial fibrillation or did they just really want to feel better after
having gone through this procedure so that they couldn't detect the difference?

The
other part of that is you're comparing one to three months of pre-data to six
months post-data.My guess would be
that as time went by the people especially the young and busy stopped making
their transmissions.

Can
you take a three month piece or a one month piece of post-procedural data and
make a comparison recognizing that one month free of atrial fibrillation means
pretty little?But is that possible to
look at that?Would the compliance be
good enough at one month or three months to make a look at that data be
worthwhile?I don't know who I'm asking
these questions to.

DR.
CALKINS:This whole event monitoring
stuff is very difficult.We have been
going around it all day.Your point
about the patients seem to be less aware of the atrial fibrillation in
follow-up.I think when you looked at
the number of transmissions baseline 50 percent of the ones were atrial
fibrillation.At the end there was
about 30 percent that transmitted atrial fibrillation.That denominator for that is the total
number of transmissions whether it's the weekly ones that not everyone
did.It's the just of the total
transmissions we had how many showed atrial fibrillation.

DR.
TRACY:These aren't symptomatic
transmissions.

DR.
CALKINS:These were the lump
transmissions is my understanding.We
just looked at all transmissions and how many of those were atrial
fibrillation.I think right now the
question is if you can put a REVEAL monitor in would that be the better
answer.It seems you need something
where the patient doesn't have to transmit himself or herself.

Dr.
Ewing said in that another study they had better compliance.I'm not sure if the other study was atrial
fibrillation or what the rhythm disorder was but I think a lot of it depends on
who the population is that we're dealing it.

I'm
not aware of better compliance in an atrial fibrillation study in a paroxysmal
population like this at six months.Maybe there are better ways to do it.We can learn from the other studies that have been done however there
may be better techniques to prod patients.

DR.
EWING:This is Lesley Ewing.I'm going to provide to Dr. Tracy the raw
data on transmissions that was submitted from Cardima to the FDA.

DR.
TRACY:Okay.I think those were my major points.I'll take a look at this but pass the question over.Are you ready?

DR.
ZUCKERMAN:Okay, before we continue now
that the clinicians have gone around for the first round.I do think it's important to clarify the
remarks made by Dr. White which were quite important because I've heard from
the clinicians, many on this side of the table and that side of the table, that
in atrial flutter line is an atrial flutter line perhaps from a clinician's
perspective.The people on this side of
the table wear a clinical, regulatory and statistical hat today.

The
bottomline is that the only atrial flutter catheter that is approved right now
by the FDA is an 8mm tip catheter.A
lot of what you've been hearing or all the 4mm tip catheters would be
considered off-label use which just underlines the point that Dr. White made
about the necessity to follow protocols once they've been developed or the
point that's made on slide nine of the FDA presentation again talking about
what the protocol was during part three of this investigation.

CHAIRMAN
LASKEY:Would you care to respond?

DR.
CALKINS:At least my interpretation of
Bram's question was more of a statement rather than a question.It is true that the only approved flutter
catheter is the 8mm catheter.It is
also true that the EP community uses whatever they like in the common
irrigating catheter and so forth to create that line.His point is well taken but I took as a statement.Bram, did you have a question specifically
that hasn't been addressed that I can answer?

DR.
ZUCKERMAN:No, it's just protocol
dictates that you have the opportunity to respond.

DR.
CALKINS:The protocol as initially
specified said initial attempts not that you create a block with the Cardima
catheter but you initially try it and then you can use another clinically
available catheter to create this part of the investigational procedure.If you look at it in that sense, there was
never anything in this protocol or the FDA had agreed, that yes, try this
catheter but you can use whatever's clinically available to do the flutter
line.That isin fact what was done.

For
the sake of patient benefit and the speed of the procedure and so forth, above
all we're taking care of patients.A
step was skipped and they did not use that first catheter. Dr.White is correct in his interpretation.But that's what was done.At the end of the day, it was taking care of
patients.

DR.
TRACY:Actually that's not at all my
understanding of what the FDA presented.I thought clearly that the option at the point where the decision was
made to permit a catheter other than linear catheter.An opportunity was given at that time to enter a contract with
another catheter manufacturer or to provide your own ablation catheter for the
study.

So
maybe there was just an enormous misunderstanding in the investigators that
they thought they could try with this and if this didn't work, then they could
go whatever happened to be their favorite catheter.Maybe somebody needs to clarify that.That definitely was not my understanding.

MS.
BALDWIN:Marianne Baldwin, Vice
President, Regulatory, Quality and Clinical at Cardima.The original protocol in Phase IIb did in
fact specify that the investigator could use standard institutional procedure
to create only the isthmus line if the linear wasn't able to do that.Now that was the approved protocol that we
went into the study with.

Actually
we had also used it in IIa.In the
course of IIb and IIa, it was made clear that we needed to have a ?- In fact let me back up just another step here
and say that in the initial development in this protocol which is to treat AF,
it was discussed and debated at some length about whether or not a flutter line
was necessary.

It
was concluded clinically that it wouldn't really be fair to a patient to go in
there and do a catheter ablation and not do the flutter line.This is irrespective of an indication for
flutter.This is to assure further
effectiveness of the atrial fibrillation treatment.In fact I think one of the investigators, one of the people
involved in the development of this protocol, said "It just wouldn't be
ethical to not include the flutter line in this treatment scenario."

At
that time, Cardima did not have a 4mm catheter.In fact as you've all heard, there was no flutter catheter
approved.So the standard institutional
procedure was an off-label catheter.There was no way to implement this protocol without that during Phase
IIb and in fact during Phase IIa.So
Cardima developed its own 4mm catheter for Phase III.

A
large number of those patients that you've seen in the study whose flutter line
was treated with a non-study catheter came from Phase IIB before the NavAblatorTM
was available.So yes, there was a lot
of confusion and by this time, a number of the investigators had been involved
in the study in Phase IIb and in Phase III, the protocol itself still said
"If you fail you still have the option of using the standard institutional
procedure" because how you can not complete the lines.How can you not complete these lesions?That's not ethical.That comprises the characteristic of the
confusion about that particular part in the protocol.

DR.
WALDO:Al Waldo.Can I just make a comment?

MS.
TILLMAN:Dr. Waldo, this is Donna
Tillman from the FDA.I just want to
make one clarification.If you look at
the FDA presentation slides seven and eight, I just want to reiterate that
nothing that we do ever is intended to interfere with the physician's ability
to treat a patient where necessary.

However
we did repeatedly instruct the company that use of non-investigational
catheters in the trial would be considered a failure.If you look at our slides, historically we've told the company
that on numerous occasions.So I think
that we need to separate what was appropriate to do in terms of treating the
patient which nobody is going to argue with the physician's best judgment
versus what FDA told the company in terms of how the data in the study would be
ultimately available.

DR.
WALDO:Can I make a comment?

DR.
TRACY:Al, the 42 percent that you reported
as your success rate that's counting those as failures.

DR.
EWING:The 42 out of 88 includes the
success of the procedure.Only 24 out
of the 88 were considered a success using only the Cardima catheter.So it's a difference in terms of evaluating
whether the procedure is a success, taking care of the patient using whatever
methods you have versus the FDA's evaluation whether a device works for that
procedure.

DR.
WALDO:Can I make a comment here?

CHAIRMAN
LASKEY:Al, hang on a second.We're just trying to handle these one at a
time because the slippery slope just got extremely slippery.We have a dialogue here but the company gets
to respond as well.I don't limit this
between Cindy and the FDA.I'll have
your response to Cindy's question.Do
you have a follow-up?I think you were
very helpful, Marianne, but do you want to further clarify this?

DR.
KAY:This is Neal Kay.Cindy, I think that this is getting at
important issues.What that percentage
of success is depends on a lot of these definitions.If you do that number, it comes out 30 something.

DR.
TRACY:Twenty something.

DR.
KAY:The question you guys are going to
have to weigh obviously is in view of everything the safety I don't think we
can argue very much about that but whether that efficacy is good enough in this
patient population.I think it's going
to be in that 40 percent range.That's
my only comment.

DR.
TRACY:So it would be 20 something
percent successful strictly by protocol.Forty something percent if you permit the non-protocol catheter.Eighty percent if you go by the company's
definition.

CHAIRMAN
LASKEY:Dr. Waldo.

DR.
WALDO:Can you hear me?

DR.
ZUCKERMAN:Yes.

DR.
WALDO:I think there's something
important to add to this.Hugh earlier
when talking about the flutter lesion I think I heard him correctly.He suggested that there was some question
about whether that was even needed.

I
think it's important to keep in mind where those other lesions are made.There's a big lesion between the vena cavi
that's made.That's a setup for making
the atrial flutter circuit.In many
ways, the atrial flutter lesion is critical to prevent the development of flutter.

In
other words, a lesion of atrial flutter isthmus is almost a requisite
regardless of whether you think it has any value in treatment symptoms per
se.It has value preventing flutter
that may be caused by one of the lesions that makes a line of block between
vena cavi.That's just a mechanistic
comment that wherever this goes that probably is an important aspect.

CHAIRMAN
LASKEY:Again you have the prerogative
of responding.

DR.
CALKINS:Al, I agree with your comment
completely and that's why when the study was designed in terms of the flutter
line, it would unethical to go in there and do an ablation procedure and not
put a flutter line in.That speaks to
Marianne's comments and the way the study was designed that the flutter line
was part of this protocol even though the REVELATION_ Tx is designed to create
linear lesions in other regions of the atrium.

DR.
WALDO:Right.

CHAIRMAN
LASKEY:All right.I think we've been around this.I suggest we take a 10 minute break.No more and then we will regroup around for
the panel process.Off the record.

(Whereupon,
the foregoing matter went off the record at 3:32 p.m. and went back on the
record at 3:45 p.m.)

CHAIRMAN
LASKEY:Back on the record.I'mon the finish line here so everybody can get to their plane.I'm going to have Geretta read the FDA
questions at this point.

MS.
WOOD:I will read each question and
then the panel members will have a chance to respond.The sponsor conducted a single arm, multi-center study.The study protocol identified three linear
ablation lesions to be performed with an optional fourth lesion.The indications for use statement is based
on the procedure dictated in the study protocol.

Question
No. 1.The sponsor presented acute
procedural data on 116 patients all of whom had the posterolateral and
posteroseptal linear lesions performed with the REVELATION_ Tx catheter.The tricuspid isthmus lesion was made with a
variety of catheters throughout the two phases of the study.Please refer to the table following
retrieved from table A-19 of the submission.A. Please discuss how the multiple catheter combinations affect the
conclusions that may be drawn from this study.'

CHAIRMAN
LASKEY:In order to help engender the
consensus process, let me just start off and say that it seems to me the entire
afternoon was spent discussing the limitations of multiple catheter
combinations as articulated by Dr. White and almost everybody else.It went from protocol violations on down
from there.Do we have any other things
to add to that consensus statement?

DR.
TRACY:No, I think that's right.I think the success rates go if you just
look at only using the protocol catheters 20 percent and if you look at
procedural success by FDA calculations 47 percent and if you look at procedural
success using the sponsor's calculation 80 percent.So again it's an issue of variation in the amount of success.

CHAIRMAN
LASKEY:So at best they confound the
interpretation of the conclusions and at worse they preclude making
conclusions.All right, B.

MS.
WOOD:Please discuss the ability to
analyze the device outcomes versus treatment outcomes in this study.In particular, can you comment on whether
the safety and effectiveness results for this study may be attributable to one
specific catheter?Do the treatment
strategies employed in the study support the proposed indications for use
statement?

CHAIRMAN
LASKEY:Well again reflecting on the
comments, I think part B stems from part A that the different treatment
strategies necessarily employed the different catheters.There are two sides of the same coin.I think the answer then will be the same.

DR.
TRACY:Except you might be a little bit
more generous saying that if you look at treatment outcome and you take the
most pessimistic analysis, it's 40 something percent treatment success.

DR.
GILLIAM:But I'm not sure you can even
say that because we're making the assumption that there is some success in the
six month follow-up.Given the
possibility of actual data, the fact that if you are making the assumption that
no news is success and it may be that no news is continued atrial fibrillation.
So my suggestion that we may be being very generous to suggest that it's
20 percent or even 40 percent.We may
even have no difference between a control group and an interaction.

CHAIRMAN
LASKEY:Dr. Waldo.

DR.
WALDO:Yes.

CHAIRMAN
LASKEY:Are you still with us?

DR.
WALDO:Is that Rosie talking?I agree with him.

CHAIRMAN
LASKEY:Thank you.

MS.
WOOD:The study identified the acute
procedural effectiveness endpoints as demonstration of either the reduction in
the amplitude, fragmentation or wideness of local electrograms or appearance of
split potentials.These endpoints were
not consistently measured and/or recorded in the data collection forms.

The
sponsor indicated in the PMA submission that no conclusion can be made about
the acute procedural success endpoint.It is unknown what measure or electrogram characteristic was used by the
individual investigator to determine when the linear lesion was completed.Therefore each investigator may have
performed a slightly different ablation procedure. Please discuss how the
lack of measurable procedural endpoint affects data analysis for this clinical trial.

CHAIRMAN
LASKEY:I think this was nicely
summarized by Dr. Maisel who wondered when to tell the operator to stop.What were the endpoints and the responses
were not crystal clear.Is that fair?

DR.
MAISEL:I agree that it seems unclear
exactly what the procedural endpoint is.You can argue that the procedure as performed and simply look at the
effectiveness data to decide if the procedure is effective with these vague and
general statements about the procedure.I think Part IIb which we'll get to in a minute is the more important
aspect of the procedural endpoint.

MS.
WOOD:Please discuss whether the study
provides sufficient information to instruct the user of the catheter system as
to procedural goals or endpoints when treating an individual patient.

DR.
MAISEL:In my mind, this is the more
important aspect of the procedural endpoints with regard to both safety and
effectiveness and the physician knowing how much to do and when to stop.

CHAIRMAN
LASKEY:Therefore does the study
provide sufficient information to instruct the user as to the goals or
endpoints when treating the individual patient?

DR.
MAISEL:I would say no.

CHAIRMAN
LASKEY:I think that reflects the
consensus of the group.

MS.
WOOD:The primary effectiveness
endpoint was based on comparing number of atrial fibrillation episodes captured
and transmitted by event recorders during a baseline period and the six month
post-procedure in patients on the same medication or a reduced dosage.It is unknown if each transmission
represented a discrete atrial fibrillation episode.Given that the patients knew that a certain amount of episodes
were required to be admitted into the study, please discuss the potential
problems with accuracy in the counting of episodes at baseline and at
follow-up.

CHAIRMAN
LASKEY:I thought the sponsor actually
answered this in a credible fashion but I'mnot sure that's the essence of getting your arms around an event which
has tremendous variability.The
variability and frequency of atrial fibrillation or just editorializing PVCs
for that matter requires a different approach.To answer your question here, there are problems with accuracy in
counting an event which is admittedly highly variable at baseline and more so
at follow-up.

DR.
WALDO:Most studies with
transtelephonic monitoring asks the patient to call back again when they think
they've been in atrial fibrillation or when they were normal rhythm.So they establish that they return to normal
rhythm so that a new episode is generally a new episode.That's part of the rigor of what we would
like to have seen here.It asks a lot
but a lot is needed.Unfortunately I
think a lot of it is missing.

DR.
GILLIAM:I would further suggest that a
Holter monitor done before and after could have added some information.Perhaps informational people were having
paroxysms so that they do have not just one episode of a persistent atrial
fibrillation.

CHAIRMAN
LASKEY:All right.Is it helpful then to say that particularly
for the follow-up period better ascertainment needs to be ensured?

DR.
TRACY:I would echo that.I think you need it for both periods because
your primary endpoint is a difference between the baseline and the follow-up.

MS.
WOOD:During the sixth month
post-procedure, the protocol required patients to transmit weekly recording and
in addition whenever they had symptoms of atrial fibrillation.Fifty-three out of 83 patients or 63.9
percent transmitted fewer than four times in the sixth month.Thus 36.1 percent of patients completely
complied with the protocol requirement.Please discuss how incomplete compliance with transmissions of rhythm
strips impacts measurement of the primary effectiveness endpoints.

CHAIRMAN
LASKEY:I think the group has said
repeatedly that it precludes interpretation of the endpoint.

MS.
WOOD:The safety endpoint was listed of
adverse events over 24 months and major complications that occurred in the
first seven days post-procedure.A
total of five out of 116, 4.7 percent, with the upper limit of 95 percent
confidence interval being 9.4 percent, patients that had a major complication
within a week of the right atrial ablation procedure.If all patients who required pacing within two weeks are
included, the major complication rate would be 6.9 percent, eight out of 116
with the upper limit of a 95 percent confidence level being 13.0 percent.Please comment on whether the results of the
clinical study provide reasonable assurance of safety for the intended use.

CHAIRMAN
LASKEY:I don't think we were as
concerned about the safety of the procedure as we were clearly efficacy.We dwelled on that but are there safety
concerns?The rates of perforation and
so forth are standard.

DR.
TRACY:I agree.The safety concerns are not great with
this.I think it's more the efficacy
that's questionable.

DR.
WALDO:Just one of the concerns by
abandoning the anterior lesion, there was some concern about getting sinus
nodes.I don't think safety concerns
are a major problem here.

MS.
WOOD:A total of 20 out of 88, 22.7
percent, patients had a permanent pacemaker implanted during the long term
follow-up period.Nine of the 20 also
had a AV node ablation procedure.In
this patient population, please comment on whether this rate of permanent pacemaker
implantation represents a significant safety concern for the device.Given the lack of a control group, please
comment on how one would determine an acceptable rate of permanent pacemaker
implantation.

DR.
TRACY:You have a comparison.You can compare to any type of surgical
intervention and see what the rates are on that.This does not seem to be out of line.Having AV node ablation represents not so much a complication as
a procedure failure and therefore 100 percent of those who have an AV node
ablation are going to end up with pacemakers.I think those are thought of differently so you are left with 17 or 20
percent.I'm not sure what the right
number is at this point.You're left
with some percent of the 20 that are having it because of sinus node
dysfunction.That's probably not out of
line with what you would see following a Maze procedure.

DR.
WALDO:In my opinion this represents
some of the problems with rigor in the study because we do know that there were
some patients who came into the study already having a pacemaker.That I think was a whole lot better in some
respects because it eliminated one of the imponderables at least for me.I think that it would have been much better
to deal with sinus node dysfunction at the beginning so that it doesn't provide
a confounding factor in this whole thing.I think that was a problem.

Whether
it's excessive I'm not sure because I think the sponsors were right that there
is a fairly high incidence of sinus node dysfunction.Some people estimate as many as two-thirds of patients with
atrial fibrillation have sinus node dysfunction.So it wasn't a surprise that these people have sinus node
dysfunction.

Then
many of the drugs that we used to treat them be the AB nodal blocking drugs or
antiarrhythmics further add to that sinus node dysfunction.I don't think it was excessive.It might seem to at first but probably it
really isn't.

CHAIRMAN
LASKEY:Are you satisfied with the
determination of an acceptable rate of permanent pacer implementation?Is that response satisfactory?Just concurrent controls or historic
controls or do you need more?

DR.
ZUCKERMAN:Unless someone has a better
way of making that comparison.Do any
of the other electrophysiologists have suggestions?

DR.
WALDO:I don't know how we can answer
that definitively but I do think if you think about it, it really probably
isn't a surprise.That would be my
surmise.

DR.
MAISEL:Maybe one other possibility
would be to do formal sinus node testing just prior to the ablation while the
catheters are in.Granted that's not
the most sensitive method for evaluating the sinus node but would be an option.

MS.
WOOD:The primary effectiveness
hypothesis was:subjects with greater
than or equal to five episodes during the 30 day baseline period.A reduction of 50 percent or more is
required to constitute a clinical success.For those subjects with three to four episodes during the baseline
period, a reduction of 75 percent is required to constitute a clinical
success.These reductions were to occur
in patients either on the same medication regime or decreased dosage.The results of the clinical study have been
described in the presentation.Do the
clinical data provide a reasonable assurance of the effectiveness of the
system?

CHAIRMAN
LASKEY:Well, very bluntly, I think
everyone up here has said no.Any
qualifications?Do you have
consensus?We have pained looks but do
we have consensus?Okay.

MS.
WOOD:Please discuss the clinical
utility of the primary endpoint of a percent decrease in atrial fibrillation
episodes as opposed to a cure for paroxysmal atrial fibrillation.Does a significant decrease in PAF episodes
constitute adequate evidence for effectiveness?

DR.
GILLIAM:I think the problem again
comes under defining whether there is a decrease.We don't have a handle on whether the numbers actually support
whether there has been any change in the frequency, duration and the burden of
atrial fibrillation post-procedure as compared with pre-procedure.

DR.
MAISEL:But I would say that the
endpoint as defined is adequate.It's
just that there wasn't evidence to support it.

DR.
GILLIAM:Yes.

DR.
WHITE:The consensus is that the
percentage would be an adequate one if you could measure it and met your
prestated goals.

CHAIRMAN
LASKEY:But we shouldn't be looking for
obliteration, a zero frequency at follow-up.We're looking for a given percent decrease.Is that right?Okay?

MS.
WOOD:A secondary effectiveness
endpoint of the study was improvement in quality of life.Given the potential bias introduced with a
nonrandomized, unblinded study, please comment on the device system's
demonstration of improvement in quality of life.

DR.
TRACY:It's all subjective.You have to have some assessment of quality
of life because you're dealing with a condition that we have pretty good data
that suggests that it's not a life-threatening arrhythmia nor is it terribly
likely to affect longevity, etc.So you
need an assessment of quality of life.No assessment of quality of life is perfect.It needs to be in there.I tend to believe that these people did feel significantly better.It's just that unfortunately we don't have a
better way of determining why they felt better.The quality of life data is fine.

CHAIRMAN
LASKEY:Yes, most of these tools were
developed in the randomized trial literature.They were not applied to single arm, unblinded trials.It makes it extremely difficult as the
statisticians said to discount placebo effect or to adjust for placebo.It's very hard.

MS.
WOOD:If you believe that additional
data are necessary to demonstrate assurance of safety and effectiveness of the
Cardima ablation system, please address the following questions.Please clarify if additional analyses on the
current data set may be performed to provide adequate information to support
safety and effectiveness.

DR.
WALDO:I have one thought on that.It's possible that if they go over that
data, there are some patients who Cardima indicates had no episodes at all of
atrial fibrillation.It would be really
nice to see how many of these patients were reliable in performing the
transtelephonic monitors.Maybe they'll
get lucky and find that they all did for instance.That would be useful.I
didn't see any of those data sorted out that way and to me that might be some
degree of important support to their contentions.

DR.
MAISEL:In addition there are still a
number of patients who apparently were enrolled in the study and have not
reached the sixth month clinical endpoint.I don't know what the status of those patients is.Certainly an effort could be make to get
full data on all of those patients.

MR.
MORTON:Dr. Laskey.

CHAIRMAN
LASKEY:Yes.

MR.
MORTON:Could I follow on a question
that you had and it had to do with looking at this PMA as it was presented to
the panel as a system.We have spent
the afternoon talking about those data especially with the catheter in
there.If we look at only the
REVELATION_ Tx microcatheter, do we have adequate data for only that device?

CHAIRMAN
LASKEY:The hooker with that as I've
come to understand is that it's felt to be now unethical.That is to just do the linear ablation
without treating the isthmus.That one
needs to do the whole thing.Is that
right?Are there people who feel
strongly about that?

DR.
MAISEL:The only other comment I would
make is the lack of effectiveness data which is true for no matter which subset
of catheters we look at.

DR.
TRACY:Yes, I think you can't just put
a couple of linear lesions in there and not do an isthmus burn.There's pretty good data that would support
the need for putting in an isthmus burn.But I think your question is not just the linear catheter but the
system.Am I interpreting it
correctly?Are there enough data on the
patients who had the system used?

But
I think it's only 24 percent of the patients that have the system used or some
percent.I doubt you'd have statistical
significance with such a small percentage of the patients.It's unlikely that the compliance was better
in those that had the total system used versus those that had a mix and match
used.I don't think there's probably
anything salvageable but it could certainly be looked at.

MS.
WOOD:Please comment if the collection
of additional data using the current patient selection criteria and outcome
measures would be adequate to support safety and effectiveness.

CHAIRMAN
LASKEY:I think Bill's comment about
trying to get better sixth month follow-up or more complete sixth month
follow-up will only help.I don't know
to what extent.I can't estimate.That's the only thing we've come up with.

DR.
SCHWARTZMAN:What about a more detailed
post hoc assessment of EKG AF burden if each of these patients were subjected
to a rigorous month of ambulatory monitoring and the company lived and died
with the result of that relative to the baseline notwithstanding the
limitations of baselines? It sounds to me like the month of baseline was
probably not the limitation.It's the
follow-up that's the problem.If we
took a snapshot month of any patient beyond six months and lived and died with
that versus the month pre-, would that be something that people would be
interested in?

DR.
MAISEL:I think it gets very
complicated when the patients are their own control.If you're not collecting data in the same way in both sides of
the procedure, then I think it gets very difficult to interpret.

DR.
SCHWARTZMAN:We would be talking about
daily transtelephonic monitoring for a month comparing that to patient's
baseline.The problem I see in that is
that they may have evolved so far away from the procedure that the drug changes
would really muddy the waters.Not
knowing that seems to me that it's not inconceivable that it would be a risk
worth taking if I were looking at from the vantage point of the company.

DR.
NORMAND:If I could comment, I think
that statistically it's somewhat of nightmare in terms of how you're actually
going to handle.You've already
collected the data at baseline using a certain mechanism.Now you're proposing a different mechanism
later on.It's only going to be on a
smaller subset of patients I think we're talking about now if we are talking
about the system versus not the system.

It
may be interesting but I think statistically given it is an observational
study, I actually think having thepatients serve as their own control is a good idea.I wouldn't take that away but because they
are using the patients as their own control that means the mechanism by which
we obtain the data and look at that difference has to be done in the same
way.So I don't think there's an easy
fix that way to use the baseline data which we have to use because the patients
have to serve as their own control.

DR.
SCHWARTZMAN:So your problem with the
baseline data relative to that proposal of 30 days of daily irregardless of
symptoms, ambulatory monitoring would be what?That the baseline data was not as ?-

DR.
NORMAND:The frequency with which
you're collecting the data at baseline is different if I'm understanding you
correctly than what you're going to do in the post-period.Moreover the mechanism by which you're going
to collect the data in the post sounds like it's going to be different.It's already fixed.It's been done in the pre-period.How that information was collected was done
in a certain way.So it's a different
mechanism.I think you adequately
characterized it as ad hoc.

DR.
SCHWARTZMAN:I respect the statistical
mischief here but frankly these are patients who had a lot of atrial arrhythmia
burden as a practicing atrial fibrillationologist.If a large majority of them had 30 days of minimal burden, I
would respect that as a clinical endpoint.

DR.
NORMAND:But I think you want to be
able to justify it scientifically.We'll have this fight.So I
disagree I guess.I agree with your
point and I just think it's going to be very challenging to justify it.

DR.
MAISEL:In potentially satisfying both
of those things if we are going to go back and monitor patients again would be
to monitor them the way it was designed for them to be monitored and just pick
a different time.So instead of at six
months do it at a year out or eighteen months or whatever we decide and then
monitor them according to the protocol.

DR.
SCHWARTZMAN:Right, but whether it's a
fixed time or anytime after six months, I don't think that it's any more
relevant to get them all to a year.I
think it's clinically relevant but in terms of answering the issue of
effectiveness, I don't think it's any more relevant to wait until they all get
to a certain point as opposed to saying again respecting the statistics any
time after six months just stop them in their tracks, do a month of ambulatory
monitoring daily and live or die by that data.

This
is not a subtle population in that regard.Unless if they have a very impressive low burden score irrespective of
how they feel assuming that the changes in drug therapy haven't muddied the
water, that to me would be convincing.

DR.
WHITE:David, the problem though is
that even if you improve the assessment mechanism, the fundamental methodology
flaw of the deviation from the protocol will make it very difficult to then
take your information and be happy with what's been done with this
catheter.So even data assessment
improvement doesn't fix the protocol deviations.

DR.
SCHWARTZMAN:This comes back to this
isthmus lesion.I have to say I side
with the group that looks at an isthmus lesion as an isthmus lesion.

DR.
WHITE:That ought to have been clear
when the protocol was designed.I think
it's hard to do it post hoc.You may be
correct but why didn't you know that when you wrote the protocol?

DR.
SCHWARTZMAN:Yes.

DR.
TRACY:You have two fundamental
problems.The isthmus problem which we
should just deal with separately but in terms of if there is something
salvageable you have 36 percent of the patients who were compliant and made the
transmissions as stated by the protocol.

As
I see it, there are two solutions to what you can do to try to meet the
prespecified endpoints.You can either
accept as Bill is suggesting taking month 11 on the patients who were not
compliant and make that be their compliant month.That's one option.The
second option would be to go and recruit an additional group of patients to
bring it up to statistically significant group of patients.So there are two fundamental ways of going
about this.

The
question for the group I guess is would a month of appropriate monitoring or an
additional two months or three months of appropriate monitoring in the cohort
that's in this study satisfy this group in terms of an effectiveness endpoint?Or do we think that we begin to run into the
ambiguities of the disease progression at some point?

DR.
WALDO:Can I make a comment?Dr. Schwartzman I think earlier commented
that he was concerned that six months wasn't enough long term follow-up.

DR.
SCHWARTZMAN:Yes, I think if anything
it puts the company at a disadvantage because in my own experience and what I
anticipate from ablation in general is that it has a time-based failure that is
progressive.I think that's in no small
part because of the issues regarding aging of the atrium plus the
co-morbidities effect on the atrium such as hypertension.

But
on the other hand to set it at a year for example if 30 or 40 or 50 percent of
their patients are months away from a year, I don't think is necessarily fair
which is why I'm saying notwithstanding the statistics and the protocol
violations related to the isthmus lesion, I don't think it would be undermined
clinically to create a snapshot wherever those patients are as long as they are
at six months.

DR.
GILLIAM:We don't really have a clear
understanding of exactly what the burden was pre-procedure.We just have essentially three transmissions
done over a 30 day period except for five people who were recycled, the very
fact that they could get nine over three months whereas the other month they
couldn't get three.

It's
just that to me this getting three transmissions with atrial fibrillation as an
entry criteria.Then if in six months,
11 months, 12 months or two months period after procedure show that we don't
get any transmissions doesn't really convince me.Let's say that a person has a relatively persistent atrial
fibrillation episode that lasts two to three days.They send in three transmissions in the study.They either get cardioverted or they
spontaneously go out of it and for the next six months they have nothing.

That
could be explained that it may be has nothing to do with that procedure or that
their medication goes up.You know as
well as I do that you could stop amiodarone today and amiodarone is not going
to get out of your system in the foreseeable future.If you add another medicine, you just in effect even though
you've technically given them less of an accelerated dose of medicine by our
standards if he's not taking amiodarone anymore but it's still there at least
for a six month period.

My
problems with it fundamentally starts with the initial data collection and
understanding just how much of an atrial fibrillation burden existed and
whether we just saw a snapshot one month later, would that be sufficient to
convince me?I'm not sure that is now.

DR.
SCHWARTZMAN:I agree with your comments
on fixing AF burden whether you define it asnumber of episodes or total duration pre-operatively.That being said having been involved with
patients that are like this, these are very symptomatic and I would call high
burden patients to be able to get the number of episodes they got within a
month assuming that they were instructed to identify individual episodes and I
have no reason to disbelieve this.That's the type of patient they were.I would say that particularly if you put stringent criteria on what we
would define effectiveness in a follow-up 30 days of daily EKG monitoring that
if they met that effectiveness number then that would be convincing to me as
being effective burden reduction.

CHAIRMAN
LASKEY:Right.That goes back to the pre/post.I think it would be hard to sell.While clinically we all understand that,
still there has to be a pre/post comparison and it's not apples and
oranges.It's apples on the front end
and oranges on the back end.That's the
problem.The horns of the dilemma.

MR.
MORTON:Just a quick comment to remind
the panel that this sponsor actually conducted the study in compliance with the
earlier panel recommendations.Out of
fairness, I know you are trying to work within so that they can salvage this.

MS.
WOOD:Please comment if a new
perspective trial is needed to provide adequate information to support safety
and effectiveness.

CHAIRMAN
LASKEY:Well, you know that's often the
easiest thing for the panel to do.I'm
not sure we suggested that up here today.We're still grappling with either how to salvage or how to dig deeper to
get some useful information here.I'm
not sure anyone is prepared to recommend.What do you think, Cindy?

DR.
TRACY:I would like to know back to
sponsor's slide 71 baseline symptomatic AF episodes per month mean is 10.1 plus
or minus 8.9.There are at least some
salvageable data here in terms of people.We have a good sense of what the atrial fibrillation burden was.I think we should be very clear that there
is a group that we can make a comparative.

I
would be willing to accept an arbitrary period of time really rein these people
in and the investigators in to get the data even if it'smonth nine to 13 or something like that on
the cohort that's present.We can see
how much can be obtained that way and/or get an additional group of people.

I
agree that this was the directive these people were given at the start of the
protocol.Here's how you will do
it.Here's how you'll assess this.So for us to recommend a change in how we
assess things at this point is not fair.We have to work with the guidelines and rules that were set up ahead of
time.I'm not talking about the flutter
burn.I'm talking about just the
guidelines in terms of symptomatic assessment.I think we have to stick with what that was at that time that the
protocol was created and try to salvage as much as we can out of that.

CHAIRMAN
LASKEY:That being said, it's very hard
to account for regression to the mean, for placebo effect, for everything else
that the statisticians pointed out are limitations perhaps unavoidable in this
kind of study.So yes, we're saddled
with this but I don't think we have to like it.

DR.
MAISEL:I would also say that
demonstration of effectiveness if new data were achieved, in my mind there are
still a number of outstanding issues.I
don't think we should be sending a message that if effectiveness is
demonstrated then we're comfortable with this.At least I'm not comfortable with some of the other issues.

DR.
WHITE:No, I think that's why we have
to suggest that a new perspective trial is necessary.I think that needs to be said.

DR.
ZUCKERMAN:Dr. Tracy, you've asked the
Agency and the sponsor to live within the rules and to understand the history
of this application.I'm looking at FDA
slide no. 9 which was the pivotal Phase III trial design which was 80 patients
using a defined system to look at results.That's what the Agency suggested and this is a hypothetical based on
what you've learned today, the Agency might still suggest that type of approach
given the other approach suggested which was to go back and to try to recall
information from perhaps what may be problematic data sets may be
problematic.Do you have a problem with
this approach as stated on slide 9?

DR.
TRACY:If I'm looking at the same slide
you're looking at, we're slipping into the isthmus question and using other
catheters.Sample size N equals 80,
Phase III. Am I looking at the right
slide?

DR.
ZUCKERMAN:Yes, I think there was
anintent with 80 patients to get a
user-defined system and look at what the results are. This was considered
the Phase III pivotal protocol.That's
what was requested.

You've
helped us perhaps today in 1) you've given us better performance estimates for
what safety should be: 2) you've stated that these present safety estimates
look okay; and 3) you've also indicated that a certain effectiveness estimate
for reduction atrial fibrillation burden of around 40 percent is acceptable
from a clinical perspective for you.If
the sponsor and the Agency chose to look at a new data set, would that be
appropriate if one were to summarize your comments today?

DR.
TRACY:Yes, I think that would be
appropriate.I don't know if you want
to grapple with the isthmus question right now or not but if you do, my
thoughts on that would be that you can't limit people to using a catheter that
they don't like.If the standard
ablation catheter that was part of this protocol is one that I've never felt or
touched, it may not be a very good catheter.What you want is a procedural success.

I
would argue that you should open the door to permitting other catheters.If you want to specify the single approved
ablation catheter for flutter as being the alternative catheter, that's fine.But I don't think you should tie people's
hands to using something they don't like.

DR.
ZUCKERMAN:Right, I think we can write
a protocol that's acceptable from a clinical perspective.The other question I have is would
effectiveness in a new protocol be acceptable if it's just a percent reduction
in symptomatic atrial fibrillation.Are
we looking also for a certain number of true cures?

CHAIRMAN
LASKEY:Percent reduction compared to
what?

DR.
ZUCKERMAN:Baseline.The primary effectiveness endpoint in this
trial was for looking at a percent reduction and thought to be clinically
useful.

CHAIRMAN
LASKEY:You don't have that information
in this data set on the front end.

DR.
ZUCKERMAN:Right.But we're referring to question 8C if in a
hypothetical context we're designing a new trial.Can you help the Agencyand the sponsor answer this question?Is a certain percent reduction as suggested by Dr. Tracy of perhaps
around 40 percent clinically useful or should there be a certain percent
reduction and a certain number of true cures?

DR.
TRACY:We don't have a standard to
measure the cures with.The best we
have is the Maze procedure or now the pulmonary vein procedure which as we've
heard there is very little randomized control information on that.So a percent reduction from my perspective
would be adequate.

DR.
MAISEL:A percent reduction in
symptomatic atrial fibrillation is clinically relevant.If there's a reduction in symptomatic atrial
fibrillation I might also expect to see a reduction in the burden of atrial
fibrillation.In my mind, the total
burden of atrial fibrillation is less subject to bias if you were doing Holter
monitoring for example.While I do
think the symptomatic endpoint is the most clinically relevant, it would be
nice to see another endpoint with that, a surrogate endpoint, to see that it
also is reduced so that the bias that might be inherent in post-procedure
monitoring might be answered by that question.

DR.
WALDO:You know I'm even a little
troubled by the concept of 40 percent.Let me tell you why.One of the
things I wondered about in reviewing all this was the fact that if I had 10
episodes of atrial fibrillation a month and I reduce them to five I guess I
would be happy that I had only five.But I wouldn't be happy that I had the five because I would be so
symptomatic.

I
think there's a question here that we really haven't addressed.You can get a number and a decreased burden
but how that translates into something meaningful is much more important.So the fact that some of these patients seem
to have a cure was a big surprise to the investigators and certainly to
me.That would be nice if some patients
had a cure.

That's
where the quality of life issue has really become important.If a 50 percent difference really makes a
difference in a patient's life, I'd like to know that.I'm not sure I learned that from this study
that that kind of difference if I go from 10 to five is that really a whole lot
better.With five terrible episodes a
month, I would think I'm still suffering.We really didn't address that too much and that has some impact to our
considerations.

DR.
TRACY:It's a subjective disease though.It's ultimately the patient who has to
choose how far they want to go in terms of achieving palliation versus cure.
So if the patient is happy with a 50 percent or a 75 percent reduction,
I'm not going to push them any further than that.

The
quality of life issues are very difficult because there isn't a placebo
group.There isn't a better way of
doing this.It would be relevant to
have if you have cure you want to know that you have a 100 percent reduction in
the episodes.I wouldn't throw that data
away but I'm not sure that I would expect that.

Even
when you are palliating patients with medication you work hard to indicate to
them that you may break through at some point and we'll deal with it at that
time.However we're necessarily going
to change the antiarrhythmics just because you have a breakthrough at six
months that we have to cardiovert you for. So it's a very complex
disease. The endpoints that we use here are different from ABNRT or WW or
something else.

DR.
GILLIAM:I agree with you fully.It's a symptomatic illness.If you can make someone feel well, that's a
big part of what we would be very happy with.But if we're going to approve an invasive procedure to go in, we need to
document that what we're doing is actually doing something very positive and
what we're seeing is not only a placebo effect.

It
would be great if we actually had some measure that showed that there was some
decrease in atrial fibrillation burden and that is actually what's causing them
to feel better.That we would be doing
something positive.That's why I would
suggest that not a cure perhaps but certainly some objective outside measure
beyond the patient that we are doing something that's good for them to decrease
their symptomatic episodes.

CHAIRMAN
LASKEY:Such as repeat
hospitalization.Al's point is well
taken that even a 70 percent reduction leaving someone with three episodes per
month requiring hospitalization once a month for cardioversion is not going to
improve things.So maybe we ought to
tack on a hard surrogate endpoint if you are going to rethink this.

DR.
GILLIAM:But I would imagine that a lot
of these people don't get hospitalized.

CHAIRMAN
LASKEY:No, but they come in to get
cardioverted.They may not get
hospitalized. They come in and get buzzed and go home.

PARTICIPANT:That's the minority.

DR.
GILLIAM:That would be easy.If it were that way, it would be fairly easy
to look at this group even in retrospect to say that these people who called in
three or four times didn't show up to the hospital three or four times.They called in.

I
guess the hard thing is that there is clearly no easy way to evaluate AF
burden.You can evaluate how many times
someone calls you and complains.You
know that a person feels better.I can
tell you that a person feels better this month as opposed to last month but I
don't know if I did anything in that intervening time to make them feel better
or if they just were just lucky this month and next month they're going to be
calling me again.

That's
the hard part of this.It's not an easy
issue that we are asking them to show.Show us that you did something with catheter or this system if you will
to make the patient better and we have to measure in some way.Certainly there are less complaints if we
were to say that.The data clearlyshowed that because they didn't call
in.That doesn't mean that the patients
were actually feeling better.

DR.
WALDO:Good points have been made and
it shows how difficult this area is.

MS.
WOOD:Labeling for a new device should
indicate which patients are appropriate for treatment, should identify
potential device related adverse events and should explain how the device
should be used to optimize its risk/benefit profile.

If
you recommend device approval, please address the following:Does the indications for use as stated
adequately define the patient population and procedural use for which the
device will be marketed?

The
Cardima Incorporated REVELATION_ Tx microcatheter ablation system is indicated
for treatment of atrial fibrillation in patients with drug refractory,
paroxysmal atrial fibrillation by mapping, pacing and ablating with a set of
continuous linear lesions in the right atrium.Based on the study results, please discuss whether the proposed
warnings, precautions and indications are acceptable?

CHAIRMAN
LASKEY:Of course we're not quite there
yet but the patient population seemed to be well defined. We didn't
quibble about the patients in the study.They were all hard core with a high burden of atrial fibrillation.From that standpoint, the labeling is
accurate.

DR.
MAISEL:I might take exception with the
use of the word "continuous" which hasn't really be demonstrated by
the data presented today.

CHAIRMAN
LASKEY:Then I'm not sure we should
have another half hour discussion about the procedural use for which the device
will be marketed.We've been talking
about the procedural use which implicit and in which is the use of alternative
catheter or off-label catheters.We're
going to have to modify that language.Any other input?

DR.
GILLIAM:I'll just echo again the
instructions again to the physicians doing the procedure.There's no clear endpoints of the linear
ablations when you are to terminate the procedure.At some point, we would have to come up with some set of
instructions for those people doing it.

DR.
WALDO:One of the honest points of this
is that it's an empiric approach that assumes that a dog is a four-legged
animal so all four-legged animals are a dog in a sense.You're going to do the same thing for
everyone.It's an inherent
limitationthat we have to accept but
that's one of the major problems in this regard too.We have to live with it at the moment but it's a real problem.

MS.
WOOD:Please discuss whether the
instructions for use adequately describe how the device should be used.

CHAIRMAN
LASKEY:EP folks?

DR.
SCHWARTZMAN:You know again as a
newcomer to this, I don't know quite how to respond.If someone gives me an approved ablation catheter for SVT, they
tell me how to hook it up and tell me I have a generator and a catheter and
they don't tell me whether I need a sheath or how to angulate to get whatever
focus I'm getting.As you know and as
I've commented on, it's doubtful to me that this catheter creates contiguous
linear lesions.

That
being said, I don't know how far one can expect a company to go in terms of
instructing how to be creative with a catheter to get the job done.That's my quandary.I think the catheter ablates.It certainly doesn't create in my mind
contiguous linear lesions but if you take that away it ablates.So how much then do you have to stipulate in
that regard?

DR.
TRACY:I think the instructions as they
are stated here are pretty specific.They take you from point A to point B.Tell you how to hook it up.Tell
you how to flush it out.Tell you how
to deliver energy.What degree.What number of seconds, etc.The only thing that perhaps is missing is
how do you know when you are done.At
some point, we might have a better way of adding that information.But just as it's stated here, I would be
able to follow this.

DR.
ZUCKERMAN:You're referring to roughly
pages four through seven of the labeling, correct?

DR.
TRACY:Yes, correct.

CHAIRMAN
LASKEY:Does the FDA have any
additional comments, questions before the vote?

DR.
ZUCKERMAN:No, we don't.

CHAIRMAN
LASKEY:Or the sponsor.

MS.
BALDWIN:Marianne Baldwin again from
Cardima.I would first of all like to
thank you for taking your time today to listen to this very complex and
difficult discussion.It hasn't been
easy and the job for you was almost as difficult as it was for us.I realize that.

We
did make every attempt to follow guidelines and work collaboratively with the
FDA.In point of fact, times have
changed and everyone has a different point of view today than they did five
years ago.But I do appreciate your
taking the time to listen to this.Thank you.

CHAIRMAN
LASKEY:Thank you.Mr. Morton.

MR.
MORTON:I'd like to thank the sponsor
and the investigators for a very good presentation.Dr. Ewing, thank you for a good review.The rest of the FDA reviewers, very good.

I
would like to bring up the point that earlier there was a comment made about a
compliance rate from another study that the FDA presented.I know that we hold sponsors to only
discussing information that is in their PMA.I would urge the panel also to limit that information.

CHAIRMAN
LASKEY:That's a point well taken.
Thank you.Dr. Hughes,

DR.
HUGHES:Thank you.Thank you for the opportunity to provide a
few comments.I too want to offer my
appreciation to the FDA staff and the sponsors as well as voting members for
delving into this very challenging issue.

The
items have been brought up very well for debate.Again as I said this is very challenging kind of decision to be
made.I feel very confident that the
appropriate decisions will be made by the panel and the FDA in their effort to
review this for the benefit of the consumer.Thank you.

CHAIRMAN
LASKEY:Thank you.Before we move to the vote, I'd like to have
another go at the open public hearing.Is there anyone who wishes to come forth and address the panel?If not, close the public hearing and have
Ms. Wood read the voting options.

MS.
WOOD:The Medical Device Amendments to
the Federal Food, Drug and Cosmetic Act (Act), as amended by the Safe Medical
Devices Act of 1990, allows the Food and Drug Administration to obtain a
recommendation from an expert advisory panel on designated medical device
premarket approval applications (PMAs) that are filed with the Agency.The PMA must stand on its own merits and
your recommendation must be supported by safety and effectiveness data in the
application or by applicable publicly available information.Safety is defined in the Act as reasonable
assurance, based on valid scientific evidence that the probable benefits to
health (under conditions on intended use) outweigh any probable risks.
Effectiveness is defined as reasonable assurance that, in a significant portion
of the population, the use of the device for its intended uses and conditions
of use (when labeled) will provide clinically significant results.

Your
recommendation options for the vote are as follows:

1.APPROVAL - If there are no conditions
attached.

2.APPROVABLE with conditions - The panel may
recommend that the PMA be found approvable subject to specified conditions,
such as physician or patient education, labeling changes, or a further analysis
of existing data.Prior to voting, all
of the conditions should be discussed by the panel.

3.NOT APPROVABLE - The panel may recommend
that the PMA is not approvable if the data DO NOT provide a reasonable
assurance that the device is safe; or if a reasonable assurance HAS NOT been
given that the device is effective; under the conditions of use prescribed,
recommended or suggested in the proposed labeling.

Following
the voting, the Chair will ask each panel member to present a brief statement
outlining the reasons for the vote.

CHAIRMAN
LASKEY:I'd like a motion on the
PMA.Anyone?Dr. Gilliam.

DR.
GILLIAM:At this time, I would move the
PMA application be voted not approvable at this time as at this point a
reasonable assurance has not been given that the device as used and directed is
effective.

CHAIRMAN
LASKEY:Is there a second?

DR.
MAISEL:Second.

CHAIRMAN
LASKEY:It has been moved and seconded
that the PMA as Geretta just stated be denied approval.Is there some further discussion?

(No
response.)

CHAIRMAN
LASKEY:Then I think we should vote on
the motion on the table starting with Dr. Tracy.

DR.
TRACY:I agree.Do you want my reasons now or are you just
taking the vote?

CHAIRMAN
LASKEY:Do we do this by hands,
Geretta?

MS.
WOOD:You can go around the table and
take the vote.

CHAIRMAN
LASKEY:So we'll do a voice vote.

DR.
TRACY:I agree that it is not
approvable.

DR.
MAISEL:William Maisel.I agree that it is not approvable.

DR.
WHITE:I agree not approvable.

DR.
GILLIAM:I agree not approvable.

DR.
NORMAND:I also agree it's not
approvable.

DR.
SCHWARTZMAN:Agree not approvable.

DR.
ZUCKERMAN:Dr. Waldo, are you there?

DR.
WALDO:I am.Not approvable.

CHAIRMAN
LASKEY:So that's seven for the
motion.Let's just go around the table
quickly and state your name please and the reasons for voting as you did.Cindy.

DR.
TRACY:Cindy Tracy.In a way it pains me to vote this way
because I think this thing will have a role in the armamentarium for treatment
of patients with atrial fibrillation but I think that there's too much
ambiguity about the effectiveness endpoint.I'm hopeful that perhaps some of the data can be salvaged and not make
it too burdensome to go forward.

DR.
MAISEL:William Maisel.I also agree.I would like to see a linear ablation catheter on the market and
hopefully this application can be salvaged but right now, I think there are too
many questions regarding the effectiveness of the device.

DR.
WHITE:My name is Chris White.I think that the methodology is the reason
why I was uncomfortable with the effectiveness.I think the assessment of endpoints was inconsistent.

DR.
GILLIAM:Roosevelt Gilliam.Likewise, I was concerned about the
effectiveness endpoints.This is a PMA
we're asked to for a new indication for a specific very common problematic
clinical entity in which we were evaluating a new catheter, the procedure
itself as well as its use in RF generators that will be varied.I think we needed to be ensured that there
was adequate efficacy demonstrated in this study. The study did not do
that.

DR.
NORMAND:Sharon-Lise Normand.My main concerns had to do with the
definition of the primary endpoint, the ascertainment of the data for the
primary endpoint and the data analysis of the data for the primary endpoint.

DR.
SCHWARTZMAN:David Schwartzman.The two issues I had were 1) the lack of
evidence that a histological endpoint consistent with the concept had been met
and 2) lack of clarity as to the electrocardiographic burden reduction.

DR.
ZUCKERMAN:Dr. Waldo.

DR.
WALDO:Yes, I think this is very
important because it was a new direction in catheter treatment of atrial
fibrillation.Sadly the rigor was
missing that we would have liked to have seen because this is potentially very
important.We just didn't get enough
data to permit us to vote favorably.There is no question in my mind that this is of interest and potentially
important but we need to be shown better data before we can vote approval.

DR.
SCHWARTZMAN:Am I allowed to ask a
question regarding the future?

CHAIRMAN
LASKEY:Yes, let me just ask Mike and
Dr. Hughes for one final comment and then we'll get back to you, Dave.Any final words, Mike?

MR.
MORTON:No.

CHAIRMAN
LASKEY:Dave.

DR.
SCHWARTZMAN:It's always been a point
of confusion to me regarding this clinical issue and I think this situation is
adequate evidence of that.Given the
fact that as Dr. Waldo mentioned that we are in an era of empiricism, it may
put an overly onerousburden on the
manufacturer technology to achieve a clinical endpoint.I wonder that an electrophysiologic endpoint
when one could be had would not be adequate as a approvable endpoint.

With
respect to this, the initial example was the isthmus lesion which is
characterizable.It's much more
difficult than we are led to believe but it is characterizable.In the future whether it's in the right or
left atrium, these things will be a characterizable siting in the left
pulmonary vein isolation.

I
wonder because we're in near of empiricism and because what will come to
fruition is an increasingly understanding as to substrate so by nature if we do
studies now, subsets of patients will benefit and other subsets won't but we
can't separate right now.Would an
electrophysiologic endpoint alone ever be adequate to achieve device approval?

CHAIRMAN
LASKEY:You mean as a surrogate for a
clinical or just in and of itself?

DR.
SCHWARTZMAN:As a surrogate for a
clinical endpoint.Safety obviously
needs to be met but safety combined with an electrophysiologic success.Would that effort be adequate?

DR.
TRACY:The real problem though is
defining even what that electrophysiologic parameter would be.We don't know if you defined that there was
block across the linear lesion if that's why it would work clinically.Maybe it's because you are cooking the
nerves.You could certainly find
something that you could look at that you could concretely measure the same way
you can concretely measure a flutter burn.

I'm
not sure that would have any relevance clinically.I don't think I would be willing to accept that as a surrogate
for effectiveness.Some clear
definition of effectiveness burden reduction something has to be a part of what
the endpoint is.

DR.
ZUCKERMAN:Right, in general it usually
works the other way around.Our
definition of effectiveness does include the requirement for clinical utility.However, after the actual carrying out of a
number of studies where we get reliable good data where we can pick an
appropriate surrogate that reliably predicts clinical utility, then we can
consider racheting back requirements.I
think we need to understand the definition of device effectiveness.

CHAIRMAN
LASKEY:At this table or in this room,
we're looking at the boundary between empiricism and metrics and that's what we
grapple with every time. That's where this is.It's a moving target but still to not abandon the metrics aspect
of what we do here.Thank you, sponsor
and colleagues on the panel. This concludes the report.Recommendations of the panel on PMA 020039
from Cardima Incorporated for the REVELATION_ Tx microcatheter with NavAblatorTM
RF system for treatment of patients with drug refractory, paroxysmal atrial
fibrillation.Again that you all for a
hard day's work.Off the record.